ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4078A>G (p.Met1360Val) (rs80338959)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000020272 SCV000658576 likely pathogenic Hyperkalemic Periodic Paralysis Type 1 2017-03-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1360 of the SCN4A protein (p.Met1360Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (rs80338959, ExAC no frequency). This variant has been reported to segregate with hyperkalemic periodic paralysis and paramyotonia congenita in a single family and another family with hyperkalemic periodic paralysis with cold-induced weakness without stiffness (PMID: 9339683, 7689382). ClinVar contains an entry for this variant (Variation ID: 21156). Experimental studies have shown that this missense change located in transmembrane in segment IV/Sl of the resulting protein showed slower time course of inactivation and faster recovery from inactivation which resulted in a larger depolarization of the cell membrane leading to myotonia (PMID: 12562902, 9339683). In summary, this variant is a rare missense change that has been reported to segregate with hyperkalemic periodic paralysis and has been shown to affect channel function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews RCV000020272 SCV000040627 pathogenic Hyperkalemic Periodic Paralysis Type 1 2016-01-28 no assertion criteria provided literature only

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