ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2770G>A (p.Val924Ile) (rs199473177)

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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041611 SCV000065307 uncertain significance not specified 2012-12-07 criteria provided, single submitter clinical testing The Val924Ile variant in SCN5A has been reported in 2/2600 individuals in a broa d, though clinically and racially unspecified control population (Kapa 2009, Kap plinger 2010). It has not been detected in large and broad European American and African American populations screened by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS) although it remains possible that it is common i n other populations. This variant is also listed in dbSNP without frequency dat a (dbSNP rs199473177). The affected amino acid is not completely conserved in ev olution with 1 species naturally carrying the variant. This raises the possibil ity that the change is milder or benign. Of note, the variant is located in a d omain that is believed to be enriched in variants that are present in controls a lthough this does not rule out a pathogenic role (Kapa2009). Additional informat ion is needed to determine clinical significance of this variant.
GeneDx RCV000041611 SCV000235418 uncertain significance not specified 2013-08-21 criteria provided, single submitter clinical testing The Val924Ile variant in the SCN5A gene has been reported as a polymorphism, identified in two individuals out of approximately 1300 healthy control individuals (Kapplinger J et al., 2010; Kapa S et al., 2009). However, Val924Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Val924Ile results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is conserved across species. In silico algorithms are not consistent in their predictions but at least two concur Val924Ile is damaging to the protein structure/function. Mutations in nearby residues (Cys915Arg, Leu917Arg, Asn927Ser, Leu928Pro) have been reported in association with arrhythmia, supporting the functional importance of this region of the protein. With the clinical and molecular information available at this time, we cannot definitively determine if Val924Ile is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238603 SCV000297009 uncertain significance Long QT syndrome 3; Brugada syndrome 2015-08-24 criteria provided, single submitter clinical testing
Invitae RCV001085097 SCV000557122 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000058525 SCV000700029 likely benign not provided 2016-11-22 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.2770G>A (p.Val924Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 18/119070 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0009805 (15/15298). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, however these classifications predate the ExAC database, when information about the occurrence of the variant in the South Asian population was not available. Considering the prevalence of the variant in the South Asian population, it was classified as likely benign.
Color RCV001179544 SCV001344234 likely benign Arrhythmia 2019-11-24 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058525 SCV000090045 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
Blueprint Genetics RCV000157486 SCV000207231 uncertain significance Ventricular tachycardia 2014-05-07 no assertion criteria provided 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.