Submissions for variant NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)

gnomAD frequency: 0.00001  dbSNP: rs397507504

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000788006	SCV000927038	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-10	reviewed by expert panel	curation	The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (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; 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): PS2, PS4, PM2, PP3, PP2.
GeneDx	RCV000518841	SCV000057358	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26817465, 29907801, 32410215, 30050098, 29493581, 36555586, 33619735)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154561	SCV000204234	likely pathogenic	Noonan syndrome	2018-02-27	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000557839	SCV000659037	pathogenic	RASopathy	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 26817465; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40485). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000557839	SCV000698061	pathogenic	RASopathy	2019-11-19	criteria provided, single submitter	clinical testing	Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The variant, c.166A>G, has been reported in the literature and by clinical laboratories in multiple individuals affected with features of Noonan Syndrome and Related Conditions (Smith_2009, Atik_2016, Leach_2018, ClinVar database). Additionally, one reportedly de novo occurrence was observed by a clinical laboratory (ClinVar database). In addition, this variant was identified at our laboratory in one patient with pulmonary stenosis and ASD. These data indicate that the variant is very likely to be associated with disease. Several mutations in neighboring codons (N58K, N58H, and N58D) have been published in association with Noonan Syndrome, emphasizing the functional importance of this residue and/or SH2 region.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely pathogenic (3x) and pathogenic (2x). Based on the evidence outlined above, the variant was re-classified as pathogenic.
Blueprint Genetics	RCV000518841	SCV000927861	likely pathogenic	not provided	2018-08-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995619	SCV001149898	likely pathogenic	Noonan syndrome 1	2018-06-06	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000995619	SCV001573019	likely pathogenic	Noonan syndrome 1	2020-03-26	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000995619	SCV002761907	pathogenic	Noonan syndrome 1	2021-11-15	criteria provided, single submitter	clinical testing	The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine at position 56 in the protein to valine. This variant is absent from population databases (PM2), but has been reported at least 4 times in the literature in patients with a clinical presentation of Noonan syndrome or RASopathy (PS4_Moderate). A different pathogenic missense change, p.Ile56Thr, has been reported before at the same amino acid position (PM5). This variant has been identified as a de novo variant in at least two affected patients with no family history of this condition (Li et al, 2020 PMID: 32410215; Brunet et al, 2021 PMID 33619735) (PS2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40485). The variant has been reported in the HGMD database: CM161482. Computational predictions support a deleterious effect on the gene or gene product (PP3).
PreventionGenetics, part of Exact Sciences	RCV003415759	SCV004109387	pathogenic	PTPN11-related condition	2023-12-07	criteria provided, single submitter	clinical testing	The PTPN11 c.166A>G variant is predicted to result in the amino acid substitution p.Ile56Val. This variant has been reported in multiple individuals with Noonan syndrome and in some of these cases was determined to have arisen de novo (Atik et al. 2016. PubMed ID: 26817465; Li et al. 2020. PubMed ID: 32410215; Brunet et al. 2021. PubMed ID: 33619735; Table S3 in Leach et al. 2019. PubMed ID: 29907801). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel on the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/variation/40485). This variant is interpreted as pathogenic.