ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.3531C>A (p.Asp1177Glu)

gnomAD frequency: 0.00001  dbSNP: rs730881049
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159181 SCV000209127 uncertain significance not provided 2013-10-24 criteria provided, single submitter clinical testing The D1177E missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. D1177E is a conservative amino acid substitution with a negatively charged, polar residue (Asp) being replaced by another negatively charged, polar residue (Glu) at a position that is conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. The NHLBI ESP Exome Variant Server reports that D1177E was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. To date, there have been no disease associated mutations reported after codon Serine 1096 in SOS1. The vast majority of missense changes in SOS1 are pathogenic; however, a small number of missense polymorphisms have been identified in this gene. Therefore, the D1177E missense substitution is interpreted as a variant of unknown significance. The variant is found in NOONAN panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001048306 SCV001212302 uncertain significance RASopathy 2019-01-03 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181555). This variant is present in population databases (rs730881049, ExAC 0.01%). This sequence change replaces aspartic acid with glutamic acid at codon 1177 of the SOS1 protein (p.Asp1177Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.
Genome-Nilou Lab RCV002467635 SCV002763564 uncertain significance Noonan syndrome 4 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467634 SCV002763565 uncertain significance Fibromatosis, gingival, 1 criteria provided, single submitter clinical testing

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