Submissions for variant NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg)

dbSNP: rs397516801

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000206837	SCV001424748	pathogenic	RASopathy	2020-06-25	reviewed by expert panel	curation	The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Finally, PTPN11 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). 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): PS4, PM6, PM1, PM2, PP1, PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037634	SCV000061296	pathogenic	Noonan syndrome	2018-05-02	criteria provided, single submitter	clinical testing	The p.Lys70Arg variant in PTPN11 has been identified in >5 individuals with clin ical features of a RASopathy, including confirmed de novo inheritance in 1 indiv idual, and segregated with disease in 3 affected relatives (LMM data, Xu 2017). This variant was absent from large population studies and is reported in ClinVar (Variation ID: 44603). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. This var iant is located in the directly interacting residues between N-SH2 and the PTPN domains, where pathogenic missense variants are common. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosom al dominant manner based upon presence in affected individuals, de novo observat ion, segregation with disease, and absence from controls. ACMG/AMP Criteria appl ied: PS4, PM1, PM2, PM6, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206837	SCV000261103	pathogenic	RASopathy	2023-04-29	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 44603). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 29084544). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 70 of the PTPN11 protein (p.Lys70Arg). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000405696	SCV000329577	pathogenic	not provided	2020-01-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29084544, 30050098, 29907801, 32037394)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206837	SCV001426844	pathogenic	RASopathy	2020-07-08	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.209A>G (p.Lys70Arg) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes (gnomAD). c.209A>G has been reported in the literature in individuals affected with and/or undergoing diagnostic evaluation for Noonan Syndrome And Related Conditions (e.g. Leach_2019, Xu_2017). At least one case of a confirmed de novo occurrence in an individual with Noonan syndrome has been reported (Xu_2017). In addition, a ClinVar submitter reports the variant in at least 5 individuals with clinical features of a RASopathy, including segregation with disease in 3 affected relatives (SCV000061296.6). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2)/likely pathogenic (n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of Pathogenic for this variant (personal communication, June 2020). Based on the evidence outlined above, the variant was re-classified as pathogenic.
Laboratory of Medical Genetics, University of Torino	RCV002464090	SCV002760128	pathogenic	LEOPARD syndrome 1	2022-11-29	criteria provided, single submitter	research
3billion	RCV003313932	SCV004013556	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044603 / PMID: 29084544). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 29084544). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000037634	SCV001132685	likely pathogenic	Noonan syndrome	2019-12-26	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000037634	SCV001438503	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing