ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)

gnomAD frequency: 0.00002  dbSNP: rs377176361
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001200229 SCV001371133 pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing SCN4A: PM1, PM2, PP1:Moderate, PS4:Moderate, PP3, PP4, PS3:Supporting
Invitae RCV001217902 SCV001389761 pathogenic Familial hyperkalemic periodic paralysis 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1455 of the SCN4A protein (p.Ile1455Thr). This variant is present in population databases (rs377176361, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of proximal myopathy and paramyotonia congenita (PMID: 28024841). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932430). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 28024841). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV001200229 SCV001476854 pathogenic not provided 2022-09-06 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 clinical features of myotonia. Additionally, in our internal patient population, this variant is statistically more frequent than in the general population. Assessment of experimental evidence suggests this variant results in abnormal protein function. Functional studies suggest complex effects on SCN4A caused by the variant, including slower current inactivation and decrease in overall current levels (PMID:28024841). The variant is located in a region that is considered important for protein function and/or structure.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001564044 SCV001787136 pathogenic Paramyotonia congenita of Von Eulenburg 2021-06-18 criteria provided, single submitter research ACMG codes: PS3; PS4M; PM1; PM2; PP1S; PP3; PP5
Revvity Omics, Revvity Omics RCV001200229 SCV002019131 likely pathogenic not provided 2023-11-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002480654 SCV002777364 pathogenic Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Familial hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16 2022-03-19 criteria provided, single submitter clinical testing
GeneDx RCV001200229 SCV003926173 likely pathogenic not provided 2022-11-15 criteria provided, single submitter clinical testing Published functional studies demonstrate destabilization in the inactivated state which is a typical pathogenic mechanism for sodium channel myotonia and paramyotonia congenita (Bednarz et al., 2017); 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: 29606556, 31127727, 28024841, 30420713)
Pars Genome Lab RCV003229884 SCV003926610 likely benign Hypokalemic periodic paralysis, type 2 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.