ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.244A>G (p.Ile82Val) (rs397517157)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038533 SCV000062211 uncertain significance not specified 2015-07-09 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ile82Val vari ant in SOS1 has been identified by our laboratory in 1 child with Shone's comple x and 1 infant with clinical features of Noonan syndrome; however, both of these individuals inherited this variant from reportedly unaffected parents. This var iant has also been identified in 2/66566 European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517157). Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, while the clinical sign ificance of the p.Ile82val variant is uncertain, the identification of this vari ant in an individual with unrelated features and inheritance from unaffected par ents suggest that it is more likely to be benign.
GeneDx RCV000680318 SCV000515707 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SOS1 gene. The I82V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This 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. This substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function. However, the I82V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000541335 SCV000659136 uncertain significance Rasopathy 2017-06-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 82 of the SOS1 protein (p.Ile82Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs397517157, ExAC 0.009%). This variant has not been reported in the literature in individuals with a SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 45351). 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: "Probably 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. In summary, this variant has uncertain impact on SOS1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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