Submissions for variant NM_000335.5(SCN5A):c.3305C>A (p.Ser1102Tyr)

gnomAD frequency: 0.02208  dbSNP: rs7626962

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001841239	SCV000050842	benign	Cardiac arrhythmia	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041615	SCV000065311	benign	not specified	2018-02-09	criteria provided, single submitter	clinical testing	p.Ser1103Tyr in exon 18 of SCN5A: This variant was present in 8% (1903/23560) of African chromosomes by the Genome Aggregation Database, including 91 homozygote s (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7626962). This variant is c lassified as benign for Mendelian disorders based upon frequency in the general population. There is some evidence that this variant could be a risk allele for arrhythmia, although this association has not been substantiated. ACMG/AMP Crite ria applied: BA1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058563	SCV000262107	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000041615	SCV000333275	benign	not specified	2015-08-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000396768	SCV000444013	likely benign	Sick sinus syndrome 1	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000304064	SCV000444014	likely benign	Progressive familial heart block, type 1A	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000363449	SCV000444015	likely benign	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755696	SCV000444016	likely benign	Long QT syndrome 3	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001094834	SCV000444017	likely benign	Brugada syndrome 1	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000368908	SCV000444018	likely benign	Ventricular fibrillation, paroxysmal familial, type 1	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000274325	SCV000444019	likely benign	Dilated cardiomyopathy 1E	2018-02-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000058563	SCV000609588	benign	not provided	2017-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041615	SCV000700031	benign	not specified	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3308C>A (p.Ser1103Tyr) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0081 in 281287 control chromosomes (in gnomAD and publication data), predominantly observed within the African subpopulation at a frequency of 0.081, including 91 homozygotes (gnomAD). The observed variant frequency within African control individuals in the gnomAD database is approximately 800 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 African origin. The variant, c.3308C>A, has been reported in the literature in individuals affected with Arrhythmia but also in controls (Splawski 2002, Chen 2002, Darbar 2008, Jeff 2011). Multiple case-control studies showed the variant to be overrepresented in African patient population (with arrhythmia, sudden cardiac death, sudden infant death syndrome) compared to control population (Splawski 2002, Sun 2002, Burke 2005, Plant 2006, and Van Norstrand 2008). However, the odds ratios from these studies are not high enough to definitely categorize the variant as a risk factor (average odds ratio 4). In addition, other variants observed in patients carrying this variant could also be considered as playing a role as a risk of arrhythmia (Jeff 2011). Publications reported evidence for an impact on ECG traits. Akylbekova 2014 demonstrated that SCN5A-1103Y was associated with QT interval prolongation and potentiated the effect of hypokalemia on QT interval prolongation (though the variant had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration and prolongation of the JT interval). Jeff 2011 showed an association for the variant with atrial related ECG traits (i.e. P wave- and PR durations; at p<1e-05), but they found no associations in their study with ventricular related ECG traits (at p<1e-04), including the QT interval. Functional studies demonstrated some impact on channel activity especially under stress conditions such as hypokalemia and low pH (Splawski 2002, Plant 2006). Splawski 2002 stated: We estimate that 4.6 million African Americans carry Y1102. Most of these individuals will never have an arrhythmia because the effect of Y1102 is subtle. However, in the setting of additional acquired risk factors, particularly common factors such as medications, hypokalemia, or structural heart disease, these individuals are at increased risk. Successful strategies for prevention, including avoidance of certain medications, maintenance of a normal serum potassium concentration, and beta-blocker therapy, are available. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and with conflicting classifications (benign/likely benign n=10, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000621429	SCV000735107	benign	Cardiovascular phenotype	2017-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755696	SCV000883128	benign	Long QT syndrome 3	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841239	SCV000902837	benign	Cardiac arrhythmia	2018-03-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000204216	SCV000987620	uncertain significance	Brugada syndrome	2023-01-26	criteria provided, single submitter	clinical testing	Risk factor for disease development: PS3_mod;PS4_mod;PP2;BS1;BS2;BP4;BP6
Athena Diagnostics	RCV000058563	SCV001145503	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000204216	SCV001338835	benign	Brugada syndrome	2020-02-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058563	SCV001474117	benign	not provided	2023-10-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000058563	SCV001935910	benign	not provided	2020-04-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24332150, 21325150, 21498565, 24951663, 16061744, 20129283, 15851227, 15992732, 18452875, 16453024, 21385947, 12193783, 31019283, 31043699, 32880476)
Fulgent Genetics, Fulgent Genetics	RCV002504776	SCV002797824	benign	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-08-02	criteria provided, single submitter	clinical testing
Cohesion Phenomics	RCV003125829	SCV003803690	benign	Primary dilated cardiomyopathy	2022-09-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149567	SCV003838882	benign	Cardiomyopathy	2021-09-22	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000058563	SCV005258479	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000009992	SCV000030213	risk factor	Long QT syndrome 3, acquired, susceptibility to	2008-04-15	no assertion criteria provided	literature only
OMIM	RCV000009993	SCV000030214	pathogenic	SUDDEN INFANT DEATH SYNDROME	2008-04-15	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058563	SCV000090083	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:12193783;PMID:15161528;PMID:19841300;PMID:20129283).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000041615	SCV000280473	uncertain significance	not specified	2015-10-15	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. SCN5A p.Ser1103Tyr (c.3308C>A), heterozygous, missense. Also reported in the literature as p.Ser1102Tyr and is catalogued in dbSNP as rs7626962. This is a previously reported variant that is common in African-Americans with allele frequency estimates ranging from 0.056 to 0.101 (Burke et al 2005, Splawski et al 2002, dbSNP). Splawski et al (2002) first reported an association with arrhythmias. They found this variant associated with arrhythmia in African Americans referred to molecular genetic testing centers because of arrhythmia or suspected risk o f arrhythmia. Of the 23 cases, 11 were heterozygotes (47.8%) and 2 were homozygotes (8.7%), while only 13 of the 100 controls were heterozygotes and none were homozygotes. This difference was statistically significant (p = 0.000028). The authors observed statistically significant linkage within one of the case families; all eleven individuals who had a prolonged QTc and/or syncope carried at least one copy of the variant (6 were homozygotes, 5 were heterozygotes). The proband in that family presented with QTc prolongation and Torsades while on amiodarone. The variant has been reported as over-represented in cases of African Americans with arrhythmias, autopsy-negative sudden death in adults and adolescents, and in SIDS (Marjamma et al 2009; Burket et al 2005; Plant et al 2006; Van Norstrand et al 2008). In vitro studies using a whole patch clamp assay showed the variant increased channel activation (Splawski et al 2002). Plant et al (2006) reported a normal in vitro phenotype under standard conditions and an LQT3-like phenotype under low pH. Taken together, these data suggest this variant can confer a mildly increased risk of arrhythmias.