Submissions for variant NM_000335.5(SCN5A):c.1993G>T (p.Ala665Ser)

dbSNP: rs756474485

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182993	SCV000235395	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 22216297, 32048431, 34127479, 33996946, 30847666)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182993	SCV000637096	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 665 of the SCN5A protein (p.Ala665Ser). This variant is present in population databases (rs756474485, gnomAD 0.07%). This missense change has been observed in individual(s) with long QT syndrome and/or unknown arrhythmia (PMID: 23631430, 30847666, 33996946, 34127479). ClinVar contains an entry for this variant (Variation ID: 201467). 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	RCV001842905	SCV000904926	uncertain significance	Cardiac arrhythmia	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 665 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 23631430, 34127479), and in an individual suspected to be affected with arrhythmia (PMID: 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 33996946) and in a healthy control individual (PMID: 22216297). This variant has been identified in 14/280364 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.
Revvity Omics, Revvity	RCV000182993	SCV003821344	uncertain significance	not provided	2020-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223785	SCV003844829	likely benign	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1993G>T (p.Ala665Ser) results in a conservative amino acid change in 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 5.2e-05 in 249002 control chromosomes, predominantly at a frequency of 0.00072 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1993G>T has been reported in the literature in individuals affected with DCM or other cardiac diseases. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV001842905	SCV004822306	uncertain significance	Cardiac arrhythmia	2024-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 665 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 23631430, 34127479), and in an individual suspected to be affected with arrhythmia (PMID: 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 33996946) and in a healthy control individual (PMID: 22216297). This variant has been identified in 14/280364 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223785	SCV000280465	uncertain significance	not specified	2014-07-30	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala665Ser (c.1993G>T) in the SCN5A gene The Ala665Ser variant has been previously reported in just one individual clinically tested for LQTS, who also carried a second variant in a different LQTS gene, and there is no segregation data available. Lieve et al. (2013) reported it in a 10 year old male with a suspected diagnosis of LQTS and a family history of LQTS. He was diagnosed at age 7 and had a mean QTc of 494 msec. According to the paper, he also had a second variant: Arg82Trp in the KCNJ2 gene. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Alanine with a polar Serine. Alanine at this location is highly conserved across mammalian species. However, this residue varies in birds, reptiles, and fish. Variation at nearby residues (+/- 10) in humans has been associated with atrial fibrillation, LQTS, or Brugada syndrome, which may support the functional importance of this region of the protein: Glu655Lys, Arg661Trp, Leu673Pro (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Benign” with a score of 0.177. It is not present in ClinVar http://www.ncbi.nlm.nih.gov/clinvar/. In total the variant has not been seen in over 6800 published controls and individuals from publicly available population datasets. It was not observed in published controls: 200 Caucasian and 100 African American (Lieve et al. 2013). There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 2/2/2015.
Clinical Genetics, Academic Medical Center	RCV000182993	SCV001921856	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182993	SCV001952106	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000182993	SCV001972043	uncertain significance	not provided		no assertion criteria provided	clinical testing