ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.749T>C (p.Leu250Pro)

dbSNP: rs1057521065
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439261 SCV000520905 likely pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SCN4A gene. The L250P variant has been previously reported as a heterozygous variant in multiple families with sodium channel myotonia (Trip et al., 2008; Stunnenberg et al., 2010). It was not observed in approximately 6,400 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 L250P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001861506 SCV002229471 pathogenic Hyperkalemic periodic paralysis 2021-04-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with sodium channel myotonia (PMID: 19876661). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381540). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 250 of the SCN4A protein (p.Leu250Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

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