Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV006342082 | SCV007215722 | likely pathogenic | Cardiovascular phenotype | 2025-11-06 | criteria provided, single submitter | clinical testing | The p.G60S variant (also known as c.178G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 178. The glycine at codon 60 is replaced by serine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with PTPN11-related RASopathy (Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Bertelloni S et al. Hormones (Athens), 2013;12:86-92; Eboreime J et al. Hum Mutat, 2022 Dec;43:2205-2221; Tabib A et al. Eur J Med Res, 2022 Dec;27:286; Abolhassani A et al. NPJ Genom Med, 2024 Feb;9:12; van der Woude S et al. J Cutan Pathol, 2025 Jan;52:20-23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic for PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is uncertain. |
| Genomic Medicine Center of Excellence, |
RCV005859477 | SCV006552459 | pathogenic | Noonan syndrome 1 | 2025-09-10 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001219186 | SCV004804000 | pathogenic | RASopathy | 2024-01-30 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.178G>A (p.Gly60Ser) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) 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 250992 control chromosomes (gnomAD). c.178G>A has been reported in the literature as de novo in individuals affected with Noonan Syndrome (example: Ezquieta_2012). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 22465605). ClinVar contains an entry for this variant (Variation ID: 40490). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Centre of Medical Genetics, |
RCV003985264 | SCV004801701 | likely pathogenic | See cases | 2023-09-04 | criteria provided, single submitter | clinical testing | ACMG categories: PS1,PM1,PM2 |
| ARUP Laboratories, |
RCV000157700 | SCV004562965 | pathogenic | not provided | 2023-09-11 | criteria provided, single submitter | clinical testing | The PTPN11 c.178G>A; p.Gly60Ser variant (rs397507507) is reported in multiple individuals with PTPN11-associated disorders and reported to occur de novo in most of these individuals (Bertelloni 2013, Ezquieta 2012). This variant is also reported in ClinVar (Variation ID: 40490). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.89). Based on available information, this variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. PMID: 23624134. Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. English, Spanish. PMID: 22465605. |
| Prevention |
RCV004532484 | SCV004118948 | pathogenic | PTPN11-related disorder | 2023-07-03 | criteria provided, single submitter | clinical testing | The PTPN11 c.178G>A variant is predicted to result in the amino acid substitution p.Gly60Ser. This variant has been reported in individuals with Noonan syndrome/RASopathy phenotypes, with at least one case confirmed to have occurred de novo (Ezquieta et al. 2012. PubMed ID: 22465605; Bertelloni et al. 2013. PubMed ID: 23624134). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different amino acid substitutions affecting the same amino acid (p.Gly60Cys, p.Gly60Ala, p.Gly60Val) have been reported in individuals with Noonan syndrome (Human Gene Mutation Database). The c.178G>A (p.Gly60Ser) variant is interpreted as pathogenic. |
| Fulgent Genetics, |
RCV002490444 | SCV002810456 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-08-01 | criteria provided, single submitter | clinical testing | |
| Kariminejad - |
RCV000157700 | SCV001755489 | likely pathogenic | not provided | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001219186 | SCV001391111 | pathogenic | RASopathy | 2025-09-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 60 of the PTPN11 protein (p.Gly60Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 22465605, 23624134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40490). 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) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 16643459, 17020470, 24039098, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000151684 | SCV000199992 | pathogenic | Noonan syndrome | 2017-07-31 | criteria provided, single submitter | clinical testing | The p.Gly60Ser variant in PTPN11 has been previously identified in three individ uals with clinical features of Noonan syndrome (Ezquieta 2012, LMM unpublished d ata), was noted to have occurred de novo in one individual, and was absent from large population studies. In addition, several other amino acid changes at this position (p.Gly60Ala, p.Gly60Cys, p.Gly60Val) have been observed in individuals with clinical features of Noonan syndrome, suggesting that changes to this resid ue are not tolerated. In summary, this variant meets our criteria to be classifi ed as pathogenic for Noonan syndrome in an autosomal dominant manner based on it s de novo occurrence, absence from large population databases and multiple varia nts affecting this codon in individuals with features of Noonan syndrome. |
| Gene |
RCV000157700 | SCV000057363 | pathogenic | not provided | 2023-04-14 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are 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: 22465605, 36349709, 23624134, 11992261, 9491886, 16053901, 29493581) |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000157700 | SCV000207686 | likely pathogenic | not provided | 2015-01-15 | no assertion criteria provided | clinical testing |