Submissions for variant NM_000335.5(SCN5A):c.612-2A>G

gnomAD frequency: 0.00002  dbSNP: rs370438420

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842459	SCV001356982	uncertain significance	Cardiac arrhythmia	2019-04-28	criteria provided, single submitter	clinical testing	This variant alters the canonical splice acceptor site in intron 5 of the SCN5A gene and is predicted to disrupt RNA splicing. Functional assays have not been performed for this variant. This variant has been reported in an individual affected with cardiac conduction disease or Brugada syndrome (Mizusawa 2016, thesis). In one family affected with Brugada syndrome, this variant did not segregate with disease (PMID: 20031634). Three of six carriers from this family showed an ECG pattern characteristic of Brugada syndrome, and three non-carriers showed ECG pattern characteristic of Brugada syndrome. This variant has also been identified in an individual affected with sudden unexplained death (PMID: 29672598). However, family screening identified two relatives with the same variant and negative cardiac symptoms. This variant has been identified in 2/233124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant affects a position that is thought to be important for RNA splicing, available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541540	SCV002240708	pathogenic	not provided	2021-09-20	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: 162501). Disruption of this splice site has been observed in individual(s) with Brugada syndrome and/or sudden unexplained death (PMID: 20031634, 29672598). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs370438420, ExAC 0.003%). This sequence change affects an acceptor splice site in intron 5 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973).
Ambry Genetics	RCV003298153	SCV003995847	likely pathogenic	Cardiovascular phenotype	2023-03-30	criteria provided, single submitter	clinical testing	The c.612-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 5 in the SCN5A gene. This variant has been detected in a Brugada syndrome cohort; however, details were limited (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). In one family, this variant was detected in three individuals with Brugada pattern on ECG and cardiac conduction disease. It was also detected in three relatives with normal ECGs, while three relatives without this variant were reported to have Brugada pattern on ECG with or without conduction disease (Probst V et al. Circ Cardiovasc Genet, 2009 Dec;2:552-7). This variant was also detected in a sudden death case and in two relatives with normal cardiac evaluation (Marcondes L et al. PLoS One, 2018 Apr;13:e0196078). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
CSER _CC_NCGL, University of Washington	RCV000149886	SCV000190587	likely pathogenic	Brugada syndrome	2014-06-01	no assertion criteria provided	research