ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3412A>G (p.Ile1138Val) (rs56248239)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587119 SCV000209085 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing The c.3412 A>G (I1138V ) variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/268,480 global alleles (0.003%) in large population cohorts (Lek et al., 2016). Multiple in silico splice prediction programs predict that the c.3412 A>G substitution creates a cryptic splice donor site upstream of the canonical splice donor site in intron 22, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the actual effect of this sequence change in this individual is unknown.If expressed and translated, the I1138V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000722119 SCV000698635 uncertain significance not specified 2018-05-07 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3412A>G (p.Ile1138Val) results in a conservative amino acid change in 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 3e-05 in 268480 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions (3e-05 vs 3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3412A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its 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 classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000697593 SCV000826213 uncertain significance Rasopathy 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1138 of the SOS1 protein (p.Ile1138Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs56248239, ExAC 0.02%). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 181544). 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 and their clinical significance is uncertain. 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, 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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