Submissions for variant NM_000335.5(SCN5A):c.2014G>A (p.Ala672Thr)

gnomAD frequency: 0.00002  dbSNP: rs199473140

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058471	SCV000235396	likely benign	not provided	2019-05-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20129283, 19841300, 25351510)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058471	SCV000637097	benign	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000058471	SCV000700023	likely benign	not provided	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.2014G>A (p.Ala672Thr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 111/140944 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.005815 (96/16510). This frequency is about 58 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been reported in the literature, mostly in controls, and without strong evidence for causality. In addition, one clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001842305	SCV000911325	benign	Cardiac arrhythmia	2018-05-29	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293134	SCV001434124	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002415516	SCV002724327	likely benign	Cardiovascular phenotype	2019-09-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058471	SCV000089991	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000212990	SCV000280466	uncertain significance	not specified	2011-04-14	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.Ala672Thr (A672T; c.2014 G>A) in the SCN5A gene This variant has not previously been reported in any individuals with LQTS or Brugada syndrome. It has, however, been seen in controls of 3 different ancestries. In total this variant has been seen in 3 out of ~8800 individuals from published controls and publicly available population datasets. In terms of Caucasian controls ethnically-matched to our patient, it has been seen in 1 out of ~5328 individuals. Kapa et al. from Ackerman’s group (2009; also Kapplinger et al. 2010) found the variant in 1 control individual of Asian ancestry out of ~1300 mixed-race controls (649 of which were Caucasian). This same paper reports that 3% of controls were positive for a variant in SCN5A. This variant is also present in 1 European American individual in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). It is present in dbSNP as rs199473140, and the source of this is 1 individual of Mexican ancestry in 1000 Genomes. (1000 Genomes contains 1092 individuals, 379 of which are of European ancestry.) GeneDx did not report controls. Variation at a nearby residues (plus or minus 10 amino acids) has been associated with disease, suggesting the possible functional importance of this region of the protein: L673P (LQT3) is in HGMD according to GeneDx; other variants include R680H (associated with SIDS; also with increased sodium current in vitro, but only under conditions of internal acidosis) and H681P (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database, citing Arnestad et al. 2007 and Priori et al. 2002). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar, hydrophobic alanine with a polar, hydrophilic threonine. The alanine at this location is not highly conserved among vertebrates; in fact, the reference amino acid is a threonine in 6 species of fish. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.005. SIFT predicts it to be “tolerated” with a score of 1.
PreventionGenetics, part of Exact Sciences	RCV004734618	SCV005354309	likely benign	SCN5A-related disorder	2024-04-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).