ClinVar Miner

Submissions for variant NM_014191.3(SCN8A):c.632T>C (p.Val211Ala) (rs1057518487)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413127 SCV000709198 uncertain significance not provided 2017-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000413127 SCV000492167 likely pathogenic not provided 2016-12-01 criteria provided, single submitter clinical testing A novel V211A variant that is likely pathogenic has been identified in the SCN8A gene. The V211A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V211A variant is a conservative amino acid substitution that occurs at a conserved position predicted to alter a residue within the S3 of the helical transmembrane region of repeat I, and in silico analysis predicts this variant is probably damaging to the protein structure/function. It has been identified as a confirmed de novo variant in a patient referred for testing at GeneDx. Therefore, we interpret V211A as a likely pathogenic variant.
Invitae RCV000699586 SCV000828304 likely pathogenic Early infantile epileptic encephalopathy 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 211 of the SCN8A protein (p.Val211Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: 29121005). ClinVar contains an entry for this variant (Variation ID: 373565). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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