ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.446G>A (p.Arg149Gln) (rs201706560)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439872 SCV000536385 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN10A gene. The R149Q variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R149Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and Glutamine is the wild-type residue at this position in multiple species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000822488 SCV000963295 uncertain significance Brugada syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 149 of the SCN10A protein (p.Arg149Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201706560, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 393033). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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