ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.571G>A (p.Glu191Lys) (rs886041241)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000293469 SCV000329528 uncertain significance not provided 2018-12-14 criteria provided, single submitter clinical testing The E191K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E191K variant has been observed at GeneDx in a patient who also harbored a variant of uncertain significance in the RAF1 gene, and had a parent who harbored both variants (clinical information not provided). The E191K 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 E191K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. While this substitution occurs at a position that is conserved across species, it is not located within a variant hot spot" or known functional domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant."
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761106 SCV000891021 uncertain significance Noonan syndrome 2020-10-07 criteria provided, single submitter clinical testing The c.571G>A missense variant has a frequency of 0.000006984 (1 of 143,180 alleles) with a maximum allele frequency of 0.00002380 (1 of 42,014) in the African subpopulation. This does not been criteria for PM2 based on ClinGen's RASopathy Expert Panel consensus methods for variant interpretation (PMID: 29493581). The p.Glu191Lys variant has been identified somatically in a patient with JMML (PMID: 29437595). The variant has also been found to segregate in a pedigree with aggressive, early-onset dilated cardiomyopathy alongside an A-band TTN truncating variant, and individuals without the SOS1 variant demonstrated reduced disease severity, thus suggesting this variant's potential involvement as a genetic risk factor for dilated cardiomyopathy in this family (PMID: 32603605). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). In ERK activation studies, the p.Glu191Lys variant increased phosphorylated ERK expression relative to wild-type levels, paralleling known disease-relevant SOS1 signaling profiles (PS3; PMID: 32603605). In summary, the clinical significance of SOS1 c.571G>A (p.Glu191Lys) is uncertain based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): PS3, PP3.
Invitae RCV001069595 SCV001234773 uncertain significance Rasopathy 2019-02-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 191 of the SOS1 protein (p.Glu191Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 40656). 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
University of Washington Center for Mendelian Genomics, University of Washington RCV001543363 SCV001761921 uncertain significance Primary dilated cardiomyopathy no assertion criteria provided research
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000293469 SCV001808850 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000293469 SCV001955585 uncertain significance not provided no assertion criteria provided clinical testing

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