ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3832G>A (p.Val1278Ile) (rs199473341)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148845 SCV000190586 likely benign Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000148845 SCV000090126 not provided Primary dilated cardiomyopathy no assertion provided literature only This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:21596231). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Color RCV000777746 SCV000913707 uncertain significance Arrhythmia 2018-09-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIII 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. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome, who also carried a pathogenic truncation variant in the same gene (PMID: 19561025). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 21596231). This variant has also been identified in 27/277114 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000183047 SCV000235456 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing The V1279I variant of uncertain significance in the SCN5A gene has been reported previously in association with Brugada syndrome and DCM (Catalano et al., 2009; McNair et al., 2011). Catalano et al. (2009) reported V1279I in one individual with Brugada syndrome who also harbored a nonsense variant in SCN5A. Subsequently, McNair et al. (2011) reported V1279I in one individual with DCM and arrhythmia. This individual had a significant family history of DCM in one sibling and conduction defects in his mother and maternal grandmother; however, it was not reported if any of these relatives also harbor V1279I (McNair et al., 2011). Additionally, the V1279I variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for arrhythmia genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The V1279I variant is observed in 27/277114 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The V1279I variant is observed in 27/277114 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The V1279I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, although this variant occurs at a highly conserved position in the S3 transmembrane helix in homologous domain III, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000553782 SCV000637142 uncertain significance Brugada syndrome 2017-10-03 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1279 of the SCN5A protein (p.Val1279Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199473341, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with dilated cardiomyopathy and an individual affected with Brugada syndrome (PMID: 21596231, 19561025). However, in the individual with Brugada syndrome, a pathogenic allele was also identified in SCN5A, which suggests that this c.3835G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 67829). This variant identified in the SCN5A gene is located in the transmembrane DIII-S3 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.