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

gnomAD frequency: 0.00001  dbSNP: rs121908551

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000396578	SCV000329511	pathogenic	not provided	2025-04-02	criteria provided, single submitter	clinical testing	Reported previously in patients with mild to moderate myotonia and diagnoses of sodium channel myotonia and paramyotonia congenita with onset in the third decade; however, no further clinical or segregation information was provided (PMID: 30611854); Published functional studies indicate V1293I alters the voltage-dependent gating behavior of SCN4A (PMID: 9660885, 30611854); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16193245, 29606556, 24939454, 28877545, 21221019, 16786525, 27486940, 28325641, 28662944, 32849172, 32660787, 8580427, 33263785, 11744749, 23771340, 24136861, 21387378, 30611854, 36796140, 9660885, 35350395)
Athena Diagnostics	RCV000396578	SCV000615090	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with paramyotonia congenita. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9660885, 30611854)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654659	SCV000776556	pathogenic	Hyperkalemic periodic paralysis	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the SCN4A protein (p.Val1293Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant paramyotonia congenita and myotonia congenita (PMID: 8580427, 23771340, 24939454, 27486940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5909). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 9660885, 11744749). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000396578	SCV001500142	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SCN4A: PP1:Strong, PM1, PM2, PS4:Moderate, PP3, PS3:Supporting
Revvity Omics, Revvity	RCV000396578	SCV002019134	pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000396578	SCV002520067	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	PP1, PP3, PM2, PS3, PS4_moderate
OMIM	RCV000006272	SCV000026454	pathogenic	Paramyotonia congenita of Von Eulenburg	1995-10-23	no assertion criteria provided	literature only
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.