Total submissions: 48
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000208002 | SCV000616375 | pathogenic | Noonan syndrome with multiple lentigines | 2017-04-03 | reviewed by expert panel | curation | The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. |
| Variantyx, |
RCV006695509 | SCV007593915 | pathogenic | Autosomal dominant PTPN11-related disorders | 2025-12-17 | criteria provided, single submitter | clinical testing | This is a nonsynonymous variant in the PTPN11 gene (OMIM: 176876). Pathogenic variants in this gene have been associated with autosomal dominant PTPN11-related disorders, including Noonan syndrome and Noonan syndrome with multiple lentigines (NSML). This variant likely occurred de novo in individuals reported in the published literature as well as a previous internal case; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 25884655) (PS2). It has been reported in many unrelated individuals affected with Noonan Syndrome/Leopard Syndrome (PMID: 12058348, 17935252, 20883402, 21365175) (PS4_Very_Strong) and has been observed to segregate with disease in at least 3 individuals from 2 families (PMID: 15520399, 20883402) (PP1). Functional studies have shown that this variant alters PTPN11 protein function (PMID: 16377799, 16638574, 18372317, 18849586) (PS3), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.965) (PP3). Moreover, the alteration lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 16377799, 18372317) (PM1). This variant has a 0.0006% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and the classification has been validated by an expert panel in ClinVar (PP5). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant PTPN11-related disorders.Inheritance from an unaffected or mildly affected parent has been reported in the PTPN11 gene, consistent with incomplete penetrance and/or variable expressivity (PMID: 20301303). |
| Department of Pediatrics, |
RCV000106323 | SCV007346505 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | This variant was classified as pathogenic according to ACMG/AMP 2015 guidelines (PMID:25741868), supported by de novo occurrence, established disease association, and location in a mutational hotspot of PTPN11. | |
| Genetic Services Laboratory, |
RCV000077851 | SCV006325505 | pathogenic | not provided | 2024-08-01 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.1403C>T, in exon 12 that results in an amino acid change, p.Thr468Met. The p.Thr468Met change affects a highly conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. The p.Thr468Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL). This pathogenic sequence change has previously been described in several individuals that meet clinical criteria for Noonan syndrome with multiple lentigines/LEOPARD syndrome (PMID: 25884655, 19864201, 20883402, 15520399, 24767283, 12058348). This variant was identified to segregate with disease in multiple families (PMID: 24767283, 15520399) and has also been identified in the assumed de novo state in two affected individuals (PMID: 25884655, 19864201). This sequence change has been described in the gnomAD database with a frequency of 0.0005% in the global population (dbSNP rs121918457). Functional studies indicate that this variant may impact the function of the PTPN11 protein (PMID: 24935154, 18372317, 16638574, 18849586). The p.Thr468Met amino acid change occurs in a region of the PTPN11 gene where other missense sequence changes have been described in individuals with Noonan spectrum disorders. These collective evidences indicate that this sequence change is pathogenic. |
| Laboratory of Genetics, |
RCV000077851 | SCV006108444 | pathogenic | not provided | 2025-02-16 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000055884 | SCV006083394 | pathogenic | LEOPARD syndrome 1 | 2025-04-30 | criteria provided, single submitter | clinical testing | Criteria applied: PS2,PS4,PP1_STR,PM5,PS3_SUP,PP2,PP3 |
| Clinical Biomedical Laboratory, |
RCV000055884 | SCV006082392 | pathogenic | LEOPARD syndrome 1 | 2025-05-12 | criteria provided, single submitter | clinical testing | This variant is predicted to substitute a threonine residue by a methionine residue. This variant is found at very low frequency in the general population databases (Genome Aggregation Database v. 2.1.1). This specific variant has been reported in the literature in patients diagnosed with Noonan and LEOPARD syndromes (PMID 18372317). In vitro functional studies provide evidence that the variant impacts protein function (PMID 18849586). |
| Juno Genomics, |
RCV000055884 | SCV005416195 | pathogenic | LEOPARD syndrome 1 | criteria provided, single submitter | clinical testing | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. | |
| Neuberg Centre For Genomic Medicine, |
RCV000106323 | SCV005374842 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | The observed missense variant c.1403C>T(p.Thr468Met) in the PTPN11 gene has been reported previously in individuals with Noonan syndrome (Athota JP et. Al., 2020, Yu ZH et al. 2014). The amino acid Thr at position 468 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Experimental studies have shown that this missense change affects PTPN11 function (Yu ZH et al. 2014). This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database (multiple submissions) as Pathogenic with a status of reviewed by expert panel. The amino acid change p.Thr468Met in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates and multiple lines of computtational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on the protein structure and function. For these reasons, this variant has been classified as Pathogenic. | |
| Genomic Medicine Center of Excellence, |
RCV000106323 | SCV004805002 | pathogenic | Noonan syndrome 1 | 2024-03-17 | criteria provided, single submitter | research | |
| Institute of Human Genetics, |
RCV000055884 | SCV004239242 | pathogenic | LEOPARD syndrome 1 | 2023-12-22 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV000106323 | SCV004177104 | pathogenic | Noonan syndrome 1 | 2023-10-23 | criteria provided, single submitter | clinical testing | The PTPN11 c.1403C>T (p.Thr468Met) variant has been reported in several individuals with clinical features of a RASopathy, and is reported to segregate with disease in at least one family (Kato H et al., PMID: 20883402; Keren B et al., PMID: 15520399; Lin IS et al., PMID: 19864201; Santoro C et al., PMID: 24767283; Spatola M et al., PMID: 25884655; Writzl K et al., PMID: 17935252). This variant has been reported in the ClinVar database as a germline pathogenic variant by many submitters, including an expert panel. This variant is only observed on 1/251,186 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a location that has been defined by the ClinGen RASopathy Expert Panel to be a hotspot or functional domain (Gelb BD et al., PMID: 29493581) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTPN11 function. In support of this prediction, functional studies show altered protein activity in several different assays (Martinelli S et al., PMID: 18372317; Oishi K et al., PMID: 18849586; Yu ZH et al., PMID: 24935154). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen RASopathy Expert Panel recommendations (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. |
| Genesolutions, |
RCV000106323 | SCV003934965 | pathogenic | Noonan syndrome 1 | 2022-06-22 | criteria provided, single submitter | clinical testing | |
| Lifecell International Pvt. |
RCV000106323 | SCV003845204 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | A Heterozygous Missense variant c.1403C>T in Exon 12 of the PTPN11 gene that results in the amino acid substitution p.Thr468Met was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 13331]. The observed variation has previously been reported for Noonan syndrome by Athota, Jeevana Praharsha, et al., 2020. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protei n function [Stewart, Rodney A., et al., 2010]. Prenatally, the diagnosis of Noonan syndrome has been suspected following certain ultrasound findings, such as cystic hygroma, increased nuchal translucency (NT) and hydrops fetalis [Lee, K. A., et al., 2009]. For these reasons this variant has been classified as Pathogenic. | |
| 3billion | RCV000106323 | SCV003841775 | pathogenic | Noonan syndrome 1 | 2025-02-14 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16638574, 18372317, 18849586, 24935154). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013331 /PMID: 12058348 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12058348, 15520399, 17935252, 19864201, 20883402, 24767283, 25884655). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15520399, 17935252, 20883402, 24767283). Different missense changes at the same codon (p.Thr468Glu, p.Thr468Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040547, VCV000265663 /PMID: 17927788). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Ambry Genetics | RCV002390104 | SCV002699162 | pathogenic | Cardiovascular phenotype | 2025-07-16 | criteria provided, single submitter | clinical testing | The p.T468M pathogenic mutation (also known as c.1403C>T), located in coding exon 12 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1403. The threonine at codon 468 is replaced by methionine, an amino acid with similar properties. This variant was identified in one or more individuals with features consistent with PTPN11-related RASopathy and segregated with disease in at least one family (Digilio MC et al. Am. J. Hum. Genet., 2002 Aug;71:389-94; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Carcavilla A et al. Eur. J. Pediatr., 2011 Aug;170:1069-74; Kindel SJ et al. J. Card. Fail., 2012 May;18:396-403). Medulloblastoma has been reported in an individual with this mutation (Rankin J et al. Am. J. Med. Genet. A, 2013 Aug;161A:2027-9). In multiple assays testing PTPN11 function, this variant showed functionally abnormal results (Hanna N et al. FEBS Lett., 2006 May;580:2477-82; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis. |
| MGZ Medical Genetics Center | RCV000106323 | SCV002580322 | pathogenic | Noonan syndrome 1 | 2022-08-09 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000208002 | SCV002557046 | pathogenic | Noonan syndrome with multiple lentigines | 2024-10-31 | criteria provided, single submitter | clinical testing | This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v4) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously classified as pathogenic by an expert panel (ClinVar). Changes at this residue are the second most common cause of Noonan syndrome (PMID: 29493581); Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Thr468Ala) and p.(Thr468Pro) have been classified as pathogenic (ClinVar); Variant affects known hotspot region or cluster of pathogenic variants (ClinGen expert panel, ClinVar); Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from threonine to methionine; This gene is associated with autosomal dominant disease; Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187); Variants in this gene are known to have variable expressivity (PMID: 20301303). |
| Center for Genomics, |
RCV000515406 | SCV002495906 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | criteria provided, single submitter | clinical testing | PTPN11 NM_002834.4 exon 12 p.Thr468Met (c.1403C>T): This variant has been reported in the literature in several individuals with Noonan syndrome with multiple lentigines and other RASopathies; it has been seen both as a de novo variant and as segregating with disease in multiple affected family members (Digilio 2002 PMID:12058348, Keren 2004 PMID:15520399, Writzl 2007 PMID:17935252, Lin 2009 PMID:19864201, Hansen 2009 PMID:19174044, Santoro 2014 PMID:24767284, Spatola 2015 PMID:25884655, Chinton 2019 PMID:31560489, Athota 2020 PMID:32164556). This variant is present in 0.009% (1/10440) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112488466-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13331). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Hanna 2006 PMID:16638574, Kontaridis 2006 PMID:16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586, Yu 2013 PMID:23457302). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. | |
| Dasa | RCV000157014 | SCV002107105 | pathogenic | Noonan syndrome | 2022-03-05 | criteria provided, single submitter | clinical testing | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24935154; 18372317; 16638574; 18849586) - PS3.The c.1403C>T;p.(Thr468Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13331; PMID: PMID 25884655; PMID: 19864201; PMID: 20883402; PMID: 15520399; PMID: 17935252; PMID: 24767283; PMID: 12058348; PMID: 15520399) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase - PMID 29493581) - PM1. This variant is not present in population databases (rs121918457- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID 25884655; 19864201; PMIDs: 20883402; 15520399; 17935252; 24767283; 12058348; 15520399) - PM6_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24767283, 17935252, 15520399, 20883402) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. |
| Genome Diagnostics Laboratory, |
RCV001813197 | SCV002060506 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2020-12-21 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000077851 | SCV001247468 | pathogenic | not provided | 2022-02-01 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000106323 | SCV001164413 | pathogenic | Noonan syndrome 1 | 2018-12-03 | criteria provided, single submitter | research | The heterozygous p.Thr468Met variant in PTPN11 was identified by our study in two unrelated individuals with Noonan syndrome. This variant has been identified in 0.004484% (1/22300) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918457). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rare disease sometimes diagnosed in adulthood. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The PTPN11 gene has a low rate of benign missense variation, raising the possibility that a change in this gene may not be tolerated. This variant has been reported as pathogenic in ClinVar (Variation ID: 13331). The p.Thr468Met variant in PTPN11 has been reported in 12 individuals with Noonan syndrome in the literature (PMID: 28681392, 27659786, 27238887, 12058348, 24767283). In summary, the p.Thr468Met variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PM6_Strong, PP1_Strong, PP2, PP3 (Richards 2015). |
| Agnes Ginges Centre for Molecular Cardiology, |
RCV000853462 | SCV000996373 | pathogenic | Hypertrophic cardiomyopathy | 2017-07-28 | criteria provided, single submitter | research | The PTPN11 Thr468Met variant has been reported in over 50 probands affected with LEOPARD syndrome and other Noonan spectrum disorders, including at least 4 de novo events and has been found to segregate in multiple families (see literature). We identified PTPN11 Thr468Met in a proband of Southern Eastern European descent who was diagnosed with atypical HCM. Sanger sequencing did not identify this variant in either the proband's mother or father, hence the variant has occurred de novo in our proband. The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.000008; http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster and PolyPhen2 predict this variant to be deleterious. Functional studies suggest that the variant results in reduced catalytic function (see literature). In summary, based on identification of the variant in multiple affected probands, the occurence of affected de novo individuals, functional studies displaying an affect on the protein function, segregation of the variant in affected family members, in silico tools in support of a deleterious affect and because missense variants in PTPN11 are a known mechanism of disease in Rasopathies, we classify PTPN11 Thr468Met as "pathogenic". |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV002390104 | SCV000740649 | pathogenic | Cardiovascular phenotype | 2023-07-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000208002 | SCV000698055 | pathogenic | Noonan syndrome with multiple lentigines | 2021-01-21 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.1403C>T (p.Thr468Met) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251186 control chromosomes (gnomAD). c.1403C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (e.g. Digilio_2002, Zenker_2004, Carcavilla_2013, Athota_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be catalytically defective, affecting SHP2 phosphatase activity and inducing a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to a mutant protein that is more readily activated (e.g. Kontaridis_2006, Yu_2014). Eighteen ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000515406 | SCV000611300 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-10-17 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000077851 | SCV000604983 | pathogenic | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | The PTPN11 c.1403C>T; p.Thr468Met variant (rs121918457) is reported in the literature in several individuals and families affected with Noonan syndrome with multiple lentigines, also known as LEOPARD syndrome, including de novo occurrences (Digilio 2002, Kato 2010, Keren 2004, Santoro 2014, Spatola 2015). This variant is also reported in ClinVar (Variation ID: 13331), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.965), and in vitro functional analyses demonstrate reduced enzyme activity (Edouard 2010, Hanna 2006, Martinelli 2008). Based on available information, this variant is considered to be pathogenic. References: Digilio MC et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002 Aug;71(2):389-94. PMID: 12058348. Edouard T et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol Cell Biol. 2010 May;30(10):2498-507. PMID: 20308328. Hanna N et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006 May 1;580(10):2477-82. PMID: 16638574. Kato H et al. Familial cases of atypical clinical features genetically diagnosed as LEOPARD syndrome (multiple lentigines syndrome). Int J Dermatol. 2010 Oct;49(10):1146-51. PMID: 20883402. Keren B et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004 Nov;41(11):e117. PMID: 15520399. Martinelli S et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008 Jul 1;17(13):2018-29. PMID: 18372317. Santoro C et al. LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies. BMC Med Genet. 2014 Apr 26;15:44. PMID: 24767283. Spatola M et al. PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain. BMC Neurol. 2015 Apr 16;15:55. PMID: 25884655. |
| Institute Of Molecular Biology And Genetics, |
RCV000106323 | SCV000494587 | pathogenic | Noonan syndrome 1 | 2016-11-16 | criteria provided, single submitter | research | The patient was diagnosed with typical signs of Noonan syndrome and hypertrophic cardiomyopathy at the age of 2 years old. |
| Institute Of Molecular Biology And Genetics, |
RCV000055884 | SCV000494585 | pathogenic | LEOPARD syndrome 1 | 2016-06-14 | criteria provided, single submitter | research | The patient was diagnosed with classical LEOPARD syndrome with hypertrophic cardiomyopathy. The pathogenic allele is inherited from mother who also has typical signs of LEOPARD syndrome but without hypertrophic cardiomyopathy. |
| Molecular Diagnostics Lab, |
RCV000077851 | SCV000265848 | likely pathogenic | not provided | 2015-10-01 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV000208002 | SCV000264160 | pathogenic | Noonan syndrome with multiple lentigines | 2015-12-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000033533 | SCV000253876 | pathogenic | RASopathy | 2026-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 468 of the PTPN11 protein (p.Thr468Met). This variant is present in population databases (rs121918457, gnomAD 0.004%). This missense change has been observed in individuals with LEOPARD syndrome and other Noonan spectrum disorders (PMID: 12058348, 21910245, 22555271, 22585553, 23813970, 24767283). ClinVar contains an entry for this variant (Variation ID: 13331). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 16638574, 18372317, 20535210, 23457302, 24935154). For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000208002 | SCV000061274 | pathogenic | Noonan syndrome with multiple lentigines | 2020-03-12 | criteria provided, single submitter | clinical testing | The p.Thr468Met variant in PTPN11 has been reported in >30 probands with clinical features of Noonan syndrome with multiple lentigines (Digilio 2002, Keren 2004, Tartaglia 2006, Cesarini 2009). It has also been shown to segregate with disease in 5 affected relatives (Digilio 2002, Keren 2004, Writzl 2007). It was absent from large population studies. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protein function (Stewart 2010). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome with multiple lentigines in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. |
| Eurofins Ntd Llc |
RCV000077851 | SCV000058283 | pathogenic | not provided | 2017-07-24 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000077851 | SCV000057438 | pathogenic | not provided | 2022-02-11 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with the T468M variant inducing a weakening of the interaction between the N-SH2 and PTP domains, which leads to a mutant protein that is more readily activated (Yu et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26607044, 26377682, 27236105, 25322695, 27484170, 17697839, 26686981, 29493581, 30025578, 28152038, 24803665, 21910245, 23813970, 20493809, 21365175, 16638574, 18372317, 18849586, 20883402, 16377799, 23457302, 22555271, 20308328, 24935154, 22585553, 25884655, 12058348, 24767283, 17935252, 27666661, 26742426, 26337637, 27659786, 26952712, 27238887, 28456002, 19174044, 29346770, 29084544, 16358218, 30762279, 29445579, 19054014, 30417923, 30050098, 31560489, 31722741, 32164556, 29907801, 31370276, 33318624, 33870545, 15520399, 32627323, 33673806, 27535533, 24077912) |
| Laboratory of Research in Genomics, |
RCV000055884 | SCV006554610 | pathogenic | LEOPARD syndrome 1 | 2025-04-08 | no assertion criteria provided | research | |
| Prevention |
RCV000723326 | SCV005360773 | pathogenic | PTPN11-related disorder | 2024-07-18 | no assertion criteria provided | clinical testing | The PTPN11 c.1403C>T variant is predicted to result in the amino acid substitution p.Thr468Met. This variant has been well documented as pathogenic in multiple unrelated individuals with Noonan syndrome with or without multiple lentigines (see for example - Digilio et al. 2002. PubMed ID: 12058348; Alfieri et al. 2011. PubMed ID: 21910245). At PreventionGenetics, we previously identified this variant in several other affected patients. Functional studies find this variant results in decreased protein tyrosine phosphatase activity inhibiting EGF-evoked Erk activation (Hanna et al. 2006. PubMed ID: 16638574; Kontaridis et al. 2006. PubMed ID: 16377799). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000077851 | SCV001969720 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000077851 | SCV001951468 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Diagnostic Laboratory, |
RCV000077851 | SCV001744565 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Molecular Genetics Laboratory, |
RCV000157014 | SCV001146853 | pathogenic | Noonan syndrome | 2020-01-17 | no assertion criteria provided | clinical testing | |
| Biochemical Molecular Genetic Laboratory, |
RCV000723326 | SCV000854720 | pathogenic | PTPN11-related disorder | 2018-07-05 | no assertion criteria provided | clinical testing | |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000077851 | SCV000207661 | pathogenic | not provided | 2015-01-15 | no assertion criteria provided | clinical testing | |
| Baylor Genetics | RCV000033533 | SCV000196651 | pathogenic | RASopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
| Institute of Molecular Pathology and Immunology of the University of Porto |
RCV000106323 | SCV000143815 | not provided | Noonan syndrome 1 | no classification provided | not provided | ||
| Gene |
RCV000055884 | SCV000086890 | not provided | LEOPARD syndrome 1 | no classification provided | literature only | ||
| OMIM | RCV000055884 | SCV000034507 | pathogenic | LEOPARD syndrome 1 | 2010-06-10 | no assertion criteria provided | literature only |