Submissions for variant NM_000335.5(SCN5A):c.535C>T (p.Arg179Ter)

dbSNP: rs1480085793

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825605	SCV000966949	likely pathogenic	Brugada syndrome	2016-09-22	criteria provided, single submitter	clinical testing	The p.Arg179X variant in SCN5A has been previously reported in 2 individuals wit h Brugada syndrome and 1 individual with long QT syndrome (Kapplinger 2009, Kawa mura 2009, Le Scouarnec 2015). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 179, which is predicted to lead to a truncated or absent protein. Variants in SCN5A are ass ociated with DCM, Brugada syndrome, Long QT syndrome, and other conduction syste m abnormalities (Olson 2005, Zimmer 2008). In summary, although additional studi es are required to fully establish its clinical significance, the p.Arg179X vari ant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194085	SCV001363349	pathogenic	Brugada syndrome (shorter-than-normal QT interval)	2019-04-08	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.535C>T (p.Arg179X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 245822 control chromosomes. c.535C>T has been reported in the literature in individuals affected with Brugada Syndrome (Kawamura_SCN5A_2009, Kapplinger_2009, LeScouarnec_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no inward sodium currents as measured in whole-cell current recordings using HEK293 cells indicating that the mutation was entirely non-functional. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001570662	SCV001383471	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 667015). This premature translational stop signal has been observed in individual(s) with Brugada syndrome or referred for longQT syndrome testing (PMID: 19075524, 19716085, 25650408). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg179*) 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).
Color Diagnostics, LLC DBA Color Health	RCV001842008	SCV001734422	pathogenic	Cardiac arrhythmia	2020-11-24	criteria provided, single submitter	clinical testing	This variant changes one nucleotide in exon 5 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant disrupted the function of the cardiac sodium channel (PMID: 19075524). This variant has been reported in individuals affected with Brugada syndrome (PMID: 19075524, 25650408, 28341781). This variant has been identified in 1/248622 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.
GeneDx	RCV001570662	SCV001794995	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 demonstrates this variant results in a non-functional sodium channel (Kawamura et al., 2009); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#667015; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33131149, 33221895, 30193851, 25650408, 30662450, 19075524, 25525159, 19716085)