Total submissions: 21
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000033531 | SCV007537823 | pathogenic | RASopathy | 2025-12-09 | reviewed by expert panel | curation | The NM_002834.5:c.1391G>C variant in PTPN11 is a missense variant predicted to cause substitution of glycine by alanine at amino acid 464 (p.Gly464Ala). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). 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). The p.Gly464Ala variant has been identified in five probands with RASopathies, of which two were reported to be de novo occurrences with confirmed parentage and one with unconfirmed parentage (PS4, PS2_VeryStrong; PMIDs:15389709, 15470362, 25937001, 29602897, 38041506). Shp2 phosphatase assay and phospho-ERK assay showed decreased EGF-stimulated Shp2 activity and increased ERK1/2 phosphorylation for the p.Gly464Ala mutant compared to wild-type (PS3_moderate; PMID: 16377799, 24935154). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (VCEP specifications version 2.3.0). |
| Variantyx, |
RCV006695514 | SCV007593914 | pathogenic | Autosomal dominant PTPN11-related disorders | 2025-09-13 | 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. Of these disorders, this variant is associated with Noonan syndrome with multiple lentigines, and has been reported in several unrelated affected individuals (PMID: 15121796, 29602897, 25937001, 35325944, 38540404) (PS4). It likely occurred de novo in at least two individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 29602897, 25937001) (PS2_Moderate). Functional studies have shown that this variant alters PTPN11 protein function (PMID: 16377799, 24718990) (PS3_Moderate) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.985) (PP3). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant PTPN11-related disorders. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000033531 | SCV005727155 | pathogenic | RASopathy | 2024-11-04 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.1391G>C (p.Gly464Ala) results in a non-conservative amino acid change located in the Protein tyrosine phosphatase, catalytic domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251186 control chromosomes. c.1391G>C has been reported in the literature in individuals affected with Noonan Syndrome (e.g. Sarkozy_2004, Willig_2015, Yoshida_2004), and also observed De Novo. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a catalytically impaired enzyme (Kontaridis_2006). The following publications have been ascertained in the context of this evaluation (PMID: 15389709, 16377799, 15121796, 25937001). ClinVar contains an entry for this variant (Variation ID: 13343). Based on the evidence outlined above, the variant was classified as pathogenic. |
| ARUP Laboratories, |
RCV000077850 | SCV004564603 | pathogenic | not provided | 2023-11-14 | criteria provided, single submitter | clinical testing | The PTPN11 c.1391G>C; p.Gly464Ala variant (rs121918469) is reported in the literature in multiple individuals and families with LEOPARD syndrome and Noonan syndrome (Baldo 2022, Nakagama 2018, Sarkozy 20004, Willig 2015). This variant is also reported in ClinVar (Variation ID: 13343). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.985). In support of these predictions, functional studies demonstrate that the variant protein has reduced catalytic activity compared to wildtype (Kontaridis 2006, Yu 2014). Based on available information, this variant is considered to be pathogenic. References: Baldo F et al. New insights on Noonan syndrome's clinical phenotype: a single center retrospective study. BMC Pediatr. 2022 Dec 24;22(1):734. PMID: 36566191. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. PMID: 16377799. Nakagama Y et al. Accelerated Cardiomyocyte Proliferation in the Heart of a Neonate With LEOPARD Syndrome-Associated Fatal Cardiomyopathy. Circ Heart Fail. 2018 Apr;11(4):e004660. PMID: 29602897. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID: 15121796. Willig LK et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377-87. PMID: 25937001. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51. PMID: 24935154. |
| Division of Human Genetics, |
RCV000033531 | SCV004034108 | pathogenic | RASopathy | 2023-07-01 | criteria provided, single submitter | research | |
| Genetics and Molecular Pathology, |
RCV001281363 | SCV002761721 | pathogenic | Noonan syndrome 1 | 2022-06-30 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002390105 | SCV002696141 | pathogenic | Cardiovascular phenotype | 2022-01-03 | criteria provided, single submitter | clinical testing | The p.G464A pathogenic mutation (also known as c.1391G>C), located in coding exon 12 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1391. The glycine at codon 464 is replaced by alanine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome), including at least three reportedly de novo cases (Sarkozy A et al. J. Med. Genet., 2004 May;41:e68; Yoshida R et al. Am. J. Med. Genet. A, 2004 Nov;130A:432-4; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Willig LK et al. Lancet Respir Med, 2015 May;3:377-87; Noll AC et al. NPJ Genom Med, 2016 Aug;1:16026; Nakagama Y et al. Circ Heart Fail, 2018 Apr;11:e004660). In addition, functional analyses demonstrated that this mutation has a dominant negative effect and causes conformational changes in the protein structure (Kontaridis MI et al. J. Biol. Chem., 2006 Mar;281:6785-92; Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Laboratory of Medical Genetics, |
RCV001281363 | SCV002577534 | pathogenic | Noonan syndrome 1 | 2022-01-18 | criteria provided, single submitter | clinical testing | PS4, PM1, PM2, PM5, PP2, PP3, PP5 |
| Ce |
RCV000077850 | SCV002063070 | pathogenic | not provided | 2021-10-01 | criteria provided, single submitter | clinical testing | |
| Genome Diagnostics Laboratory, |
RCV001813203 | SCV002060462 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2019-06-18 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000077850 | SCV002019558 | pathogenic | not provided | 2020-04-07 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV000077850 | SCV001714429 | pathogenic | not provided | 2022-05-13 | criteria provided, single submitter | clinical testing | PS3, PS4_moderate, PM1, PM2, PP2, PP3 |
| Hudson |
RCV001281363 | SCV001468660 | pathogenic | Noonan syndrome 1 | 2020-11-02 | criteria provided, single submitter | research | ACMG codes:PS4, PS1, PM2, PP5 |
| Labcorp Genetics |
RCV000033531 | SCV000549989 | pathogenic | RASopathy | 2025-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 464 of the PTPN11 protein (p.Gly464Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LEOPARD syndrome and Noonan syndrome (PMID: 15121796, 15389709, 16358218, 18678287, 19020799, 25937001). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13343). 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, 24935154). For these reasons, this variant has been classified as Pathogenic. |
| Center for Pediatric Genomic Medicine, |
RCV000077850 | SCV000281117 | pathogenic | not provided | 2014-08-26 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000824746 | SCV000203928 | pathogenic | Noonan syndrome with multiple lentigines; Noonan syndrome | 2014-03-04 | criteria provided, single submitter | clinical testing | The p.Gly464Ala variant in PTPN11 has been reported in at least 2 individuals wi th clinical features of Noonan syndrome or LEOPARD syndrome (Ko 2008, Ferrero 20 08, Kitsiou-Tzeli 2006). In addition, this variant has been identified by our la boratory in 2 individuals with clinical features of a Noonan spectrum disorder. It was absent from large population studies. Furthermore, functional studies sug gest this variant has a dominant negative effect, which is an established pathog enic mechanism in LEOPARD syndrome (Kontaridis 2006, Edouard 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan or LEO PARD syndrome in an autosomal dominant manner (http://www.partners.org/personali zedmedicine/LMM). |
| Eurofins Ntd Llc |
RCV000077850 | SCV000058282 | pathogenic | not provided | 2013-03-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000077850 | SCV000057436 | pathogenic | not provided | 2021-12-15 | criteria provided, single submitter | clinical testing | Reported in association with Noonan syndrome with multiple lentigines (NSML and formerly called LEOPARD syndrome) and Noonan syndrome (Sarkozy et al., 2004; Ko et al., 2008; Ferrero et al., 2008); Published functional studies demonstrate expression of this variant results in reduced catalytic activity (Kontaridis et al., 2006; Yu et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17453145, 16804314, 24935154, 24718990, 16377799, 24790373, 25937001, 19020799, 15121796, 18678287, 27484170, 27666661, 16358218, 15389709, 30105547, 29263817, 30896080, 29602897, 33318624, 32746448, 29493581) |
| Prevention |
RCV004532346 | SCV004737634 | pathogenic | PTPN11-related disorder | 2024-02-02 | no assertion criteria provided | clinical testing | The PTPN11 c.1391G>C variant is predicted to result in the amino acid substitution p.Gly464Ala. This variant is well documented to be causative in patients with Noonan syndrome with or without multiple lentigines (Sarkozy et al. 2004. PubMed ID: 15121796; Willig et al. 2015. PubMed ID: 25937001; Yu et al. 2019. PubMed ID: 30896080; Yoshida et al. 2004. PubMed ID: 15389709; Tartaglia et al. 2005. PubMed ID: 16358218; Ferrero et al. 2008. PubMed ID: 18678287; Ko et al. 2008. PubMed ID: 19020799). Consistent with other PTPN11 variants that cause Noonan syndrome with multiple lentigines, functional studies found this variant results in a loss of catalytic activity that results in a dominant negative effect (Kontaridis et al. 2006. PubMed ID: 16377799; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. |
| Gene |
RCV000055883 | SCV000086889 | not provided | LEOPARD syndrome 1 | no classification provided | literature only | ||
| OMIM | RCV000055883 | SCV000034520 | pathogenic | LEOPARD syndrome 1 | 2004-11-01 | no assertion criteria provided | literature only |