Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000610147 | SCV000731482 | pathogenic | Brugada syndrome | 2018-07-06 | criteria provided, single submitter | clinical testing | The p.Arg535X variant in SCN5A has been reported in at least 9 individuals (8 w ith Brugada syndrome and 1 referred for Long QT syndrome testing), and segregate d with disease in 4 affected relatives from 1 family (Smits 2002, Keller 2005, P robst 2009, Meregalli 2009, Kapplinger 2010, Lieve 2013). This variant has been reported in ClinVar (variation ID: 517279) and has been identified in 1/17212 Ea st Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org/). This nonsense variant leads to a premature termination codo n at position 535, which leads to a truncated protein that lacks WT function as shown by in vitro studies (Keller 2005). Heterozygous loss of function variants in the SCN5A gene have been reported in individuals with Brugada syndrome (Kappl inger 2010), DCM (Olson 2005), ventricular fibrillation (Chen 1998), as well as AV block and cardiac conduction defects (Baruteau 2012). In summary, this varian t meets criteria to be classified as pathogenic for Brugada syndrome in an autos omal dominant manner based upon segregation studies, presence in affected indivi duals and, functional evidence. ACMG/AMP criteria applied: PVS1, PM2, PS4_Modera te, PP1 (Richards 2015). |
Ambry Genetics | RCV000617180 | SCV000738079 | pathogenic | Cardiovascular phenotype | 2018-12-10 | criteria provided, single submitter | clinical testing | The p.R535* pathogenic mutation (also known as c.1603C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1603. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in several Brugada syndrome (BrS) cohorts and has been shown to segregate with disease in one family (Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46). It has also been detected in long QT syndrome (LQTS) and sudden infant death syndrome (SIDS) cohorts (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Winkel BG et al. Heart Rhythm. 2015;12:1241-9). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV001008643 | SCV000816703 | pathogenic | not provided | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg535*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with SCN5A-related arrhythmia (PMID: 12106943, 20129283, 23631430). ClinVar contains an entry for this variant (Variation ID: 517279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000845417 | SCV000987486 | pathogenic | Primary familial dilated cardiomyopathy | criteria provided, single submitter | clinical testing | ||
Gene |
RCV001008643 | SCV001168417 | pathogenic | not provided | 2021-10-25 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on channel function (Keller et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 517279; ClinVar); This variant is associated with the following publications: (PMID: 19606473, 23631430, 25525159, 19251209, 20129283, 28482396, 31043699, 30193851, 31447099, 33131149, 20031634, 15890323, 30662450, 34135346, 33087929, 12106943) |
Color Diagnostics, |
RCV001841781 | SCV001733982 | pathogenic | Cardiac arrhythmia | 2023-10-03 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 12 of the SCN5A gene, creating a premature translation stop signal. A functional study has shown that this variant results in a truncated protein and leads to a complete loss of sodium current (PMID: 15890323). This variant has been reported in over ten individuals affected with Brugada syndrome (PMID: 12106943, 15890323, 16643399, 19251209, 20031634, 32893267, 35331424) or suspected of having Brugada syndrome (PMID: 20129283, 35352813), and in an individual affected with sudden infant death syndrome (PMID: 25757662). This variant has been identified in 1/247858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
Ai |
RCV001008643 | SCV002503542 | pathogenic | not provided | 2021-05-07 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV003314626 | SCV004014731 | pathogenic | SCN5A-Related Disorders | 2023-03-20 | criteria provided, single submitter | clinical testing | The SCN5A c.1603C>T (p.Arg535Ter) nonsense variant results in the substitution of arginine at amino acid position 535 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, this variant has been identified in at least ten unrelated individuals - seven with Brugada syndrome, and one each with long QT syndrome, sudden infant death syndrome, and sudden adult cardiac death (PMID: 12106943; PMID: 15890323; PMID: 20031634; PMID: 20129283; PMID: 23631430; PMID: 25757662; PMID: 34076677). Segregation of the variant with the disorder was noted in at least one family (PMID: 20031634). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000056 in the East Asian population (version 2.1.1). Based on the available evidence, the c.1603C>T (p.Arg535Ter) variant is classified as pathogenic for SCN5A-related disorders. |