Submissions for variant NM_000335.5(SCN5A):c.2597C>T (p.Ser866Leu)

gnomAD frequency: 0.00004  dbSNP: rs755194086

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654424	SCV000637106	uncertain significance	not provided	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 866 of the SCN5A protein (p.Ser866Leu). This variant is present in population databases (rs755194086, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 32009526). ClinVar contains an entry for this variant (Variation ID: 463312). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001841462	SCV001735195	uncertain significance	Cardiac arrhythmia	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 866 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiomyopathy (PMID: 32009526). This variant has been identified in 7/282626 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002431592	SCV002742996	uncertain significance	Cardiovascular phenotype	2024-06-04	criteria provided, single submitter	clinical testing	The p.S866L variant (also known as c.2597C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2597. The serine at codon 866 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in a cardiomyopathy subset of an electronic medical records review cohort; however, clinical details were not provided (Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483408	SCV002782779	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317264	SCV004020419	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2597C>T (p.Ser866Leu) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2597C>T has been reported in the literature as a VUS in an individual with a diagnosis of cardiomyopathy who underwent whole genome sequencing as part of a study examining genome sequencing in a diverse biobank cohort, however no further clinical or genetic information was provided for this individual (Pottinger_2020). This report does not provide unequivocal conclusions about association of the variant with cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32009526). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004537960	SCV004120307	uncertain significance	SCN5A-related disorder	2023-03-29	criteria provided, single submitter	clinical testing	The SCN5A c.2597C>T variant is predicted to result in the amino acid substitution p.Ser866Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38627372-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001841462	SCV004828372	uncertain significance	Cardiac arrhythmia	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 866 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiomyopathy (PMID: 32009526). This variant has been identified in 7/282626 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.