Submissions for variant NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser)

dbSNP: rs397507507

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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has been previously identified in three individ uals with clinical features of Noonan syndrome (Ezquieta 2012, LMM unpublished d ata), was noted to have occurred de novo in one individual, and was absent from large population studies.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.
Invitae	RCV001219186	SCV001391111	pathogenic	RASopathy	2023-09-21	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. 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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000157700	SCV001755489	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490444	SCV002810456	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-08-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390716	SCV004118948	pathogenic	PTPN11-related condition	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.
ARUP Laboratories, Molecular Genetics and Genomics, 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.
Institute of Human Genetics, University Hospital Muenster	RCV003985264	SCV004801701	likely pathogenic	See cases	2023-09-04	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM1,PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157700	SCV000207686	likely pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing