ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile) (rs121908551)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000396578 SCV000615090 pathogenic not provided 2015-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000396578 SCV000329511 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing The V1293I pathogenic variant in the SCN4A gene segregates with autosomal dominant SCN4A-related disorders in many affected individuals from several families in published literature (Koch et al., 1995; Chung et al., 2016; Matthews et al., 2017). Functional studies indicate V1293I alters the voltage-dependent gating behavior of SCN4A (Green et al., 1998). The V1293I variant is not observed in large population cohorts (Lek et al., 2016). The V1293I variant is a conservative amino acid substitution. We interpret V1293I as a pathogenic variant.
GenomeConnect, ClinGen RCV000509130 SCV000606996 not provided SCN4A-related disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000654659 SCV000776556 pathogenic Hyperkalemic Periodic Paralysis Type 1 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1293 of the SCN4A protein (p.Val1293Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with paramyotonia congenita (PMID: 8580427, 24939454) and myotonia congenita (PMID: 27486940). It has also been reported in several unrelated individuals with myotonia congenita (PMID: 23771340). ClinVar contains an entry for this variant (Variation ID: 5909). Experimental studies have shown that this missense change results in a protein with altered sodium gating properties (PMID: 9660885, 11744749). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006272 SCV000026454 pathogenic Paramyotonia congenita of von Eulenburg 1995-10-23 no assertion criteria provided literature only

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