Submissions for variant NM_002834.5(PTPN11):c.166A>G (p.Ile56Val) (rs397507504)

Total submissions: 7

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	likely pathogenic	not provided	2017-07-26	criteria provided, single submitter	clinical testing	The I56V missense substitution has been observed previously in a patient with suspected Noonan syndrome (Atik et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). I56V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position within the SH2 domain that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (T52I, N58H/D/K, T59A, G60C/S/A, D61H/N/G/A) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare 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	2019-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 56 of the PTPN11 protein (p.Ile56Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a single family affected with Noonan syndrome (NS) (PMID: 26817465) and has also been observed to be de novo in an individual affected with NS (Invitae). ClinVar contains an entry for this variant (Variation ID: 40485). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	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,Klinikum rechts der Isar	RCV000995619	SCV001149898	likely pathogenic	Noonan syndrome 1	2018-06-06	criteria provided, single submitter	clinical testing