ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.3971G>A (p.Arg1324Lys) (rs761654525)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189143 SCV000242775 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing The R1324K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1324K 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). This substitution alters a highly conserved position in the predicted cytoplasmic loop between the transmembrane segments S4 and S5 of the third homologous domain of the SCN2A protein. Additionally, multiple missense variants in nearby residues (R1319Q; M1323V; V1326D; L1330F) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2009), supporting the functional importance of this region of the protein. However, the R1324K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 variant or a rare benign variant.

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