ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.931A>G (p.Met311Val)

gnomAD frequency: 0.00001  dbSNP: rs774939392
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412738 SCV000491056 uncertain significance not specified 2015-08-26 criteria provided, single submitter clinical testing The M311V variant has been published previously in a patient with a Noonan-spectrum disorder in cis with the PTPN11 Y63C variant (Ezquieta et al., 2012). The authors of this study suggested M311V is a polymorphism based on in silico predictions. The M311V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M311V variant 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 tyrosine protein-phosphatase domain where amino acids with similar properties to methionine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, and missense variants in nearby residues (N308D/T/S, I309V) 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000412738 SCV000709730 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: in ClinVar -VUS by GeneDx, not in HGMD or Google search; in 7/246208 total chrs in GnomAd
Invitae RCV000701867 SCV000830689 uncertain significance RASopathy 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 311 of the PTPN11 protein (p.Met311Val). This variant is present in population databases (rs774939392, gnomAD 0.009%). This missense change has been observed in individual(s) with PTPN11-related conditions (PMID: 22465605). ClinVar contains an entry for this variant (Variation ID: 372668). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002318367 SCV000850126 uncertain significance Cardiovascular phenotype 2016-08-04 criteria provided, single submitter clinical testing The p.M311V variant (also known as c.931A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 931. The methionine at codon 311 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in cis with a known PTPN11 mutation, p.Y63C (c.188A>G) in several individuals with suspected Noonan syndrome from two unrelated families (Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Collazo J et al. Rev Esp Cardiol (Engl Ed), 2012 Mar; Volume3N1) ).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002481274 SCV002775484 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2022-04-06 criteria provided, single submitter clinical testing

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