Submissions for variant NM_000335.5(SCN5A):c.2114C>T (p.Ser705Phe)

gnomAD frequency: 0.00001  dbSNP: rs199473148

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059141	SCV001223753	uncertain significance	Brugada syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 705 of the SCN5A protein (p.Ser705Phe). This variant is present in population databases (rs199473148, gnomAD 0.06%). 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: 67715). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	RCV001842313	SCV001344563	uncertain significance	Cardiac arrhythmia	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 705 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 with suspected Brugada syndrome (PMID: 36354768), as well as in a few healthy individuals (PMID: 19841300, 20129283). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified 13/280672 chromosomes (12/19534 East Asian 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.
All of Us Research Program, National Institutes of Health	RCV001842313	SCV004843650	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 705 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 with suspected Brugada syndrome (PMID: 36354768), as well as in a few healthy individuals (PMID: 19841300, 20129283). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified 13/280672 chromosomes (12/19534 East Asian 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058482	SCV000090002	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).