ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)

dbSNP: rs80338792
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479620 SCV000567468 pathogenic not provided 2021-05-13 criteria provided, single submitter clinical testing Reported previously as a heterozygous variant in two unrelated families with paramyotonia congenita (McClatchey et al., 1992); Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 8308722, 1310898, 27415035, 26944947, 18337100, 18337730, 28150151, 26885337, 26080010, 22094069, 20445432, 17823953, 16832098, 8044656, 16392038, 7473241, 32849172, 32660787)
Athena Diagnostics Inc RCV000479620 SCV000615092 pathogenic not provided 2023-05-03 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 associates with paramyotonia congenita in multiple families, and is reported in multiple other unrelated individuals with non-dystrophic myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038).
Invitae RCV000690377 SCV000818060 pathogenic Familial hyperkalemic periodic paralysis 2023-08-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Val). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1310898, 8044656, 8308722, 17823953, 18337100, 18337730, 20445432, 22094069, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5903). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7980103, 16832098, 20713951, 25088311, 25311598, 26080010, 26885337, 26944947). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000479620 SCV001249362 pathogenic not provided 2023-07-01 criteria provided, single submitter clinical testing SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000690377 SCV001370154 pathogenic Familial hyperkalemic periodic paralysis 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3.
MGZ Medical Genetics Center RCV000006264 SCV002581212 pathogenic Paramyotonia congenita of Von Eulenburg 2021-10-25 criteria provided, single submitter clinical testing
3billion RCV000006264 SCV003841909 pathogenic Paramyotonia congenita of Von Eulenburg 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005903). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 27415035). Different missense changes at the same codon (p.Gly1306Ala, p.Gly1306Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005908, VCV000005920). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000006264 SCV000026446 pathogenic Paramyotonia congenita of Von Eulenburg 2009-05-01 no assertion criteria provided literature only
OMIM RCV000006265 SCV000026447 pathogenic Potassium-aggravated myotonia 2009-05-01 no assertion criteria provided literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences RCV002267601 SCV002549812 pathogenic SCN4A-related non-dystrophic myotonia 2022-04-06 no assertion criteria provided research

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.