Submissions for variant NM_000335.5(SCN5A):c.1891-8G>A

gnomAD frequency: 0.00013  dbSNP: rs12720064

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151791	SCV000200247	uncertain significance	not specified	2017-11-06	criteria provided, single submitter	clinical testing	The c.1891-8G>A variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 10/23702 of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs12720064). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1891-8G>A variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richar ds 2015).
GeneDx	RCV000151791	SCV000514540	likely benign	not specified	2017-06-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654210	SCV000557146	likely benign	not provided	2025-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151791	SCV000920190	uncertain significance	not specified	2017-10-10	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.1891-8G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/270732 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000422 (10/23702). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, two clinical diagnostic laboratories classified this variant as likely benign and one other lab classified it as uncertain significance, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001842472	SCV001350898	likely benign	Cardiac arrhythmia	2018-10-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842472	SCV004814428	likely benign	Cardiac arrhythmia	2024-01-03	criteria provided, single submitter	clinical testing
Roden Lab, Vanderbilt University Medical Center	RCV004698471	SCV005200401	likely benign	Brugada syndrome 1		criteria provided, single submitter	research	We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868). The SCN5A variant, 3-38599058-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome. This Variant had an AF of 0.000118295 in gnomAD v3. The in silico predictor SpliceAI scored the variant as 0.01; normal <0.2, likely damaging >0.5. Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as LB using these collective data.
PreventionGenetics, part of Exact Sciences	RCV004734710	SCV005362304	likely benign	SCN5A-related disorder	2024-08-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).