Submissions for variant NM_000335.5(SCN5A):c.865G>A (p.Gly289Ser)

gnomAD frequency: 0.00001  dbSNP: rs199473084

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791871	SCV000931138	uncertain significance	Brugada syndrome	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 289 of the SCN5A protein (p.Gly289Ser). This variant is present in population databases (rs199473084, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 28469501). ClinVar contains an entry for this variant (Variation ID: 68050). 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	RCV001842414	SCV001341295	uncertain significance	Cardiac arrhythmia	2021-09-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 289 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 referred for long QT syndrome genetic test (PMID:19716085) and in an individual affected with sudden death (PMID: 28469501). This variant has been identified in 4/249170 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	RCV000786217	SCV001874741	uncertain significance	not provided	2021-09-07	criteria provided, single submitter	clinical testing	Reported in association with LQTS and sudden unexplained death (SUD) in published literature (Kapplinger et al., 2009; Hata et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32268277, 28469501, 19716085, 25637381, 22581653)
All of Us Research Program, National Institutes of Health	RCV001842414	SCV004825041	uncertain significance	Cardiac arrhythmia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 289 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 referred for long QT syndrome genetic test (PMID:19716085) and in an individual affected with sudden death (PMID: 28469501). This variant has been identified in 4/249170 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	RCV004019064	SCV004944537	uncertain significance	Cardiovascular phenotype	2021-02-21	criteria provided, single submitter	clinical testing	The c.865G>A (p.G289S) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 865, causing the glycine (G) at amino acid position 289 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058853	SCV000090373	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148864	SCV000190608	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786217	SCV000924948	uncertain significance	not provided	2017-12-04	no assertion criteria provided	provider interpretation	p.Gly289Ser (G289S; c.865G>A) in exon 7 of the SCN5A gene Chromosome location 3:38651294 C / T Based on the lack of case data, the variability of this residue across species, and presence of this variant in gnomAD, we classify it as a VUS. This variant has not previously been reported in a clinically-confirmed case of LQTS or Brugada syndrome. Our patient does not have a clear clinical diagnosis either. Hata et al. (2017) reported this variant in the SUD case of a 28-year-old Japanese woman who was found in a hot bath with autopsy evidence of drowning and alcohol detected on blood toxicology. This variant was also reported by Kapplinger et al. (2009) in one patient tested for LQTS at Familion. (This is most likely our patient, as medical records indicate that her LQTS testing was sent to Familion.) However, in a 2015 paper by the same group involving “enhanced classification” of SCN5A variants, p.Gly289Ser is listed as having been found in 0 LQTS patients, 0 Brugada patients, and 1 control (out of 8975). All 7 in silico prediction models used for this later study predicted the variant to be benign. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar glycine with a polar serine. The Glycine at location 289 is poorly conserved across species. In fact, Serine is the default amino acid in at least one mammalian species and in several species of bird and reptile. According to Kapplinger et al. (2009), this codon is in the DI-S5/S6 region of the protein. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 5 amino acids to either side, indicating that this region of the protein might be tolerant of change. This variant was reported in 4 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 African-ancestry (MAF 0.013%) and 2 non-Finnish European-ancestry individuals (MAF 0.0018%) in the gnomAD database. Overall MAF 0.0016%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.