ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.865G>A (p.Gly289Ser) (rs199473084)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148864 SCV000190608 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
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.
Invitae RCV000791871 SCV000931138 uncertain significance Brugada syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 289 of the SCN5A protein (p.Gly289Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs199473084, ExAC 0.02%). This variant has been observed in an individual referred for testing for long QT syndrome (PMID: 19716085) and in an individual who suffered a sudden unexpected death (PMID: 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
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.

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