Submissions for variant NM_000334.4(SCN4A):c.4774A>G (p.Met1592Val)

dbSNP: rs80338962

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516497	SCV000615104	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple families and individuals with periodic paralysis, including at least one de novo case. This variant is primarily associated with cases presenting with hyperkalemic periodic paralysis (hyperKPP; PMID: 15534250), however rare cases of normokalemic periodic paralysis (normoKPP) are also reported (PMID: 29930533). Assessment of experimental evidence suggests this variant results in abnormal protein function. Patch-clamp studies demonstrate the variant modifies activation of mutant sodium channels (PMID: 9886942). Introduction of this variant in mice produces characteristics of hyperKPP (PMID: 18317596, 21708955, 24714718).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006256	SCV000658587	pathogenic	Hyperkalemic periodic paralysis	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1592 of the SCN4A protein (p.Met1592Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SCN4A-related conditions (PMID: 1659668, 8242056, 9131651, 18046642, 21665479, 23801527, 24943082). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5897). 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 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 24714718). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763018	SCV000893469	pathogenic	Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000516497	SCV001248151	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	SCN4A: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000516497	SCV001715456	pathogenic	not provided	2020-08-21	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PP1, PP3
GeneDx	RCV000516497	SCV001872619	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant impairs slow inactivation of the sodium channel (Hayward et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24943082, 19290024, 24714718, 21404612, 32327288, 1659668, 10227633, 31068157, 21665479, 32849172, 31567646, 29930533, 23801527, 18046642, 20301669)
Fulgent Genetics, Fulgent Genetics	RCV005016245	SCV005649642	pathogenic	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal	2024-05-20	criteria provided, single submitter	clinical testing
OMIM	RCV000006256	SCV000026438	pathogenic	Hyperkalemic periodic paralysis	1997-03-01	no assertion criteria provided	literature only
OMIM	RCV000006257	SCV000026439	pathogenic	Paramyotonia congenita/hyperkalemic periodic paralysis	1997-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000006256	SCV000040634	not provided	Hyperkalemic periodic paralysis		no assertion provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000006256	SCV002600048	pathogenic	Hyperkalemic periodic paralysis	2022-04-12	no assertion criteria provided	research