ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.1333G>C (p.Val445Leu) (rs121908552)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516348 SCV000615061 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
Invitae RCV000559054 SCV000658516 likely pathogenic Hyperkalemic Periodic Paralysis Type 1 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 445 of the SCN4A protein (p.Val445Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with myotonia congenita (PMID: 27199537, Invitae). ClinVar contains an entry for this variant (Variation ID: 448262). 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"). The p.Val445 amino acid residue in SCN4A has been determined to be clinically significant (PMID: 22653516, 25839108, 25724373, 9392583). This suggests that variants that disrupt this residue are likely to be causative of disease. 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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