Submissions for variant NM_000334.4(SCN4A):c.3917G>C (p.Gly1306Ala)

gnomAD frequency: 0.00001  dbSNP: rs80338792

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153907	SCV000331588	pathogenic	not provided	2014-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000153907	SCV000567665	pathogenic	not provided	2021-02-25	criteria provided, single submitter	clinical testing	Published functional studies indicate that this variant impairs fast inactivation as compared to wild type (Lerche et al., 1993); Predicted to be within the intracellular loop between the third and fourth homologous domain; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32369273, 25525159, 7980103, 8308722, 31307605, 29774303, 28877545, 32849172, 32670189, 26080010, 31544778, 26885337, 32660787, 32528171)
Invitae	RCV000525753	SCV000658571	pathogenic	Hyperkalemic periodic paralysis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Ala). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individual(s) with myotonia fluctuans (PMID: 7980103, 8308722, 26080010, 26885337). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5908). 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: 8308722, 16832098, 17823953, 20713951). 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.
Athena Diagnostics Inc	RCV000153907	SCV000843673	pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in individuals with myotonia and segregates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7473241, 8740371, 16392038).
CeGaT Center for Human Genetics Tuebingen	RCV000153907	SCV001249363	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SCN4A: PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Revvity Omics, Revvity	RCV000153907	SCV002020018	pathogenic	not provided	2022-11-24	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288470	SCV002580167	likely pathogenic	Potassium-aggravated myotonia	2022-06-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000153907	SCV004026054	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing
OMIM	RCV001799587	SCV000026453	pathogenic	Myotonia fluctuans	1994-11-01	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV001535772	SCV001749917	not provided	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-18-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.