ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3946C>G (p.His1316Asp) (rs371024396)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159185 SCV000209131 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing The H1316D variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H1316D variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The H1316D 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in NOONAN panel(s).
Invitae RCV000461078 SCV000553265 uncertain significance Rasopathy 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 1316 of the SOS1 protein (p.His1316Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs371024396, ExAC 0.02%) but has not been reported in the literature in individuals with a SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 181557). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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