Submissions for variant NM_000335.5(SCN5A):c.1901C>T (p.Ser634Leu)

gnomAD frequency: 0.00003  dbSNP: rs568517614

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001585934	SCV001199354	uncertain significance	not provided	2023-12-14	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 634 of the SCN5A protein (p.Ser634Leu). This variant is present in population databases (rs568517614, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 835186). 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	RCV001842586	SCV001355781	uncertain significance	Cardiac arrhythmia	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 634 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/277078 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.
GeneDx	RCV001585934	SCV001819311	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002409363	SCV002722633	uncertain significance	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The p.S634L variant (also known as c.1901C>T), located in coding exon 12 of the SCN5A gene, results from a C to T substitution at nucleotide position 1901. The serine at codon 634 is replaced by leucine, an amino acid with dissimilar properties, and is located in the DI/DII interdomain linker region. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV003329171	SCV004035999	uncertain significance	SCN5A-Related Disorders	2023-04-06	criteria provided, single submitter	clinical testing	The SCN5A c.1901C>T (p.Ser634Leu) missense variant results in the substitution of serine at amino acid position 634 with leucine. To our knowledge, this variant has not been reported in association with disease in the peer-reviewed literature. This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.0001974 in the South Asian population (version 2.1.1). Based on the available evidence, the c.1901C>T (p.Ser634Leu) variant is classified as a variant of uncertain significance for SCN5A-related disorders.