ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5326G>A (p.Val1776Met) (rs199473314)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058770 SCV000090290 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:11463728;PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Color RCV000777476 SCV000913338 uncertain significance Arrhythmia 2018-07-23 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal region of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown that homozygote and heterozygote expression of the mutant allele causes a persistent inward sodium channel current (PMID: 11463728). However, clinical significance of these observations is not clear. This variant has been reported in two individuals with long QT syndrome (PMID: 11463728, 19841300). In one of these subjects the variant was found in the homozygous state, while both parents and two siblings were heterozygous carriers (PMID: 11463728). This variant has also been identified in 5/277202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000183114 SCV000235524 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing The V1777M variant in the SCN5A gene has been reported previously in the homozygous state in a symptomatic child with AV conduction disturbances (Lupoglazoff et al., 2001). Both parents and two siblings of the child were asymptomatic and heterozygous for V1777M variant, with no family history of sudden death, suggesting a low penetrance in the heterozygous state (Lupoglazoff et al., 2001). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The V1777M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect and in vitro studies of the homozygous and heterozygous states resulted in a persistent inward sodium current (Lupoglazoff et al., 2001). However, this variant lacks observation in a significant number of affected individuals, segregation data, and definitive functional evidence, which would further clarify its pathogenicity.
Invitae RCV000638654 SCV000760192 uncertain significance Brugada syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1777 of the SCN5A protein (p.Val1777Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs199473314, ExAC 0.01%). This variant has been reported in an individual referred for with long QT syndrome (LQTS) testing, (PMID:19716085) and in individuals with LQTS, including an observation of the variant in the homozygous state in one individual with LQTS and 2:1 AV block (PMID: 19841300, 11463728). ClinVar contains an entry for this variant (Variation ID: 67984). Experimental studies have shown that this missense change results in a persistent inward sodium channel current (PMID: 11463728). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.