Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Variantyx, |
RCV006695593 | SCV007593895 | pathogenic | Autosomal dominant PTPN11-related disorders | 2025-05-20 | 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. This variant likely occurred de novo in individuals reported in the published literature and previous internal cases; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 31324109, 19020799 ) (PS2_Very_Strong). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 11992261) (PM1) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.707) (PP3). This variant has a 0.0017% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). 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 variable expressivity (PMID: 20301303, 39596579, 352464530). |
| Institute for Genomic Medicine |
RCV006554514 | SCV007449269 | pathogenic | Noonan syndrome 1 | 2024-08-21 | criteria provided, single submitter | clinical testing | This variant has been reported to occur de novo in an affected individual in the literature with parental identity confirmed (ACMG/AMP: PS2; PMID:19020799). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_Supporting; PMID:19020799). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2). This variant occurs in a gene with a low rate of benign missense variation, in which missense alterations are a common mechanism of disease (ACMG/AMP: PP2). |
| Fulgent Genetics, |
RCV005003613 | SCV005632272 | likely pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2024-04-25 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000390743 | SCV005439226 | likely pathogenic | not provided | 2024-05-29 | criteria provided, single submitter | clinical testing | Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 24803665, 31324109, 34315577, 37595579, 19020799, 11992261, 9491886, 16053901, 29493581) |
| Ambry Genetics | RCV004021238 | SCV004934878 | uncertain significance | Cardiovascular phenotype | 2024-01-10 | criteria provided, single submitter | clinical testing | The c.175A>G (p.T59A) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 175, causing the threonine (T) at amino acid position 59 to be replaced by an alanine (A). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250992) total alleles studied. The highest observed frequency was 0.006% (1/16256) of African alleles. This variant has been determined to be the result of a de novo mutation in one individual with features consistent with PTPN11-related RASopathy (Ko, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Prevention |
RCV004529475 | SCV004110052 | uncertain significance | PTPN11-related disorder | 2023-02-23 | criteria provided, single submitter | clinical testing | The PTPN11 c.175A>G variant is predicted to result in the amino acid substitution p.Thr59Ala. This variant has been reported in individuals with Noonan syndrome (Ko et al. 2008. PubMed ID: 19020799; Matyášová et al. 2019. PubMed ID: 31324109). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-112888159-A-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Labcorp Genetics |
RCV001349385 | SCV001543728 | pathogenic | RASopathy | 2025-06-02 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 59 of the PTPN11 protein (p.Thr59Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19020799, 31324109). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 288033). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Eurofins Ntd Llc |
RCV000390743 | SCV000342019 | uncertain significance | not provided | 2017-10-31 | criteria provided, single submitter | clinical testing |