ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2165G>A (p.Arg722Lys) (rs142666652)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552706 SCV000659134 uncertain significance Rasopathy 2017-05-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 722 of the SOS1 protein (p.Arg722Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs142666652, ExAC 0.02%) but has not been reported in the literature in individuals with a SOS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001175591 SCV001339235 likely benign not specified 2020-03-10 criteria provided, single submitter clinical testing Variant summary: SOS1 c.2165G>A (p.Arg722Lys) results in a conservative amino acid change located in the Ras-like guanine nucleotide exchange factor, N-terminal domain (IPR000651) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250558 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7.7- fold the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2165G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating an impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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