ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1867T>G (p.Phe623Val) (rs727505093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156537 SCV000206256 likely pathogenic Noonan syndrome 2017-04-26 criteria provided, single submitter clinical testing The p.Phe623Val variant in SOS1 occurred de novo in 1 individual with clinical f eatures of a RASopathy (LMM data) and has been reported in ClinVar (Variation ID 179739). This variant was absent from large population studies. An additional a mino acid change at this position (p.Phe623Ile) was identified in two probands w ith clinical features of Noonan syndrome, which occured de novo in 1 of these in dividuals with confirmed paternity (Zenker 2007, Fabretto 2010). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Phe623Val variant is l ikely pathogenic.
GeneDx RCV000414349 SCV000491061 likely pathogenic not provided 2015-09-22 criteria provided, single submitter clinical testing A novel F623V variant that is likely pathogenic was identified in the SOS1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The F623V 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 variant, located in the the N-terminal Ras-GEF domain, is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (F623I) and nearby (V624F) residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome and hypertrophic cardiomyopathy, respectively (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000770761 SCV000698620 uncertain significance not specified 2019-02-26 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1867T>G (p.Phe623Val) results in a non-conservative amino acid change located in the N-terminal Ras-like guanine nucleotide exchange factor domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant was absent in 276468 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1867T>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. However, a variant at the same codon (p.Phe623Ile) has been reported in individuals in association with Noonan syndrome, including one de novo occurrence (Fabretto_2010, Zenker_2007), suggesting the location to be important for protein function. Substitution of the Phe623 residue by another amino acid has been hypothesized to cause altered guanine nucleotide exchange activity of SOS1 and perturb the catalytic activity of the CDC25 domain (Lepri_2011, Zenker_2007) (ACMG PM5). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. One of these assessments mentions a "reportedly" de-novo occurrence of this variant in one individual with clinical features of RASopathy although we do not have independent evidence to corroborate. This variant was identified once in our laboratory in an adult female patient tested on a panel for Noonan syndrome and related disorders. A definitive clinical indication was not provided, the patient is lost to follow-up and no additional testing has been performed. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information (i.e., clinical and functional studies) becomes available.
Invitae RCV000793245 SCV000932590 uncertain significance Rasopathy 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 623 of the SOS1 protein (p.Phe623Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 179739). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the Phe623 amino acid residue in SOS1 have been observed in affected individuals (PMID: 20673819, 17586837). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

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