ClinVar Miner

Submissions for variant NM_014191.4(SCN8A):c.2533T>C (p.Ser845Pro) (rs1057518356)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413870 SCV000491919 likely pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing A novel variant that is likely pathogenic has been identified in the SCN8A gene. The S845P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S845P 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 conserved position within the transmembrane segment S4 voltage sensor of the second homologous domain. Missense variants in nearby residues (F846S and R850Q) have been reported in the Human Gene Mutation Database in association with SCN8A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts the S845P variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.

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