Submissions for variant NM_000334.4(SCN4A):c.2411C>T (p.Ser804Phe)

dbSNP: rs121908546

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489309	SCV000577654	likely pathogenic	not provided	2015-08-07	criteria provided, single submitter	clinical testing	The S804F variant in the SCN4A gene has been reported in a family segregating an autosomal dominant form of myotonia with overlapping features of paramyotonia congenita and myotonia congenita. This variant was found to co-segregate with the phenotype in all family members tested and was not observed in 100 control chromosomes (McClatchey et al., 1992). The S804F variant was not observed in approximately 6,200 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 S804F variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (A799S) has been reported in the Human Gene Mutation Database in association with severe neonatal episodic laryngospasm (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S804F as a strong candidate for a disease-causing variant; however, the possibility it may be a rare benign variant cannot be excluded
Athena Diagnostics	RCV000489309	SCV001879486	pathogenic	not provided	2021-03-23	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to disrupt skeletal muscle sodium channel inactivation through alterations in voltage dependent gating. (PMID: 9618291, 9660885, 10682917)
Revvity Omics, Revvity	RCV000489309	SCV002019132	likely pathogenic	not provided	2021-02-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003505081	SCV004297513	pathogenic	Hyperkalemic periodic paralysis	2023-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 804 of the SCN4A protein (p.Ser804Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant paramyotonia congenita and/or myotonia congenita (PMID: 1338909, 7980103). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5901). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN4A function (PMID: 9618291, 10682917, 11744749, 16392038). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000006261	SCV000026443	pathogenic	Paramyotonia congenita/myotonia congenita	1994-11-01	no assertion criteria provided	literature only
OMIM	RCV001799586	SCV000026444	pathogenic	Myotonia fluctuans	1994-11-01	no assertion criteria provided	literature only