ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3305C>A (p.Ser1102Tyr) (rs7626962)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171820 SCV000050842 benign Cardiac arrhythmia 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare 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
Invitae RCV000204216 SCV000262107 benign Brugada syndrome 2020-12-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000041615 SCV000333275 benign not specified 2015-08-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000396768 SCV000444013 likely benign Sick sinus syndrome 1, autosomal recessive 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000363449 SCV000444015 likely benign Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000368908 SCV000444018 likely benign Paroxysmal familial ventricular fibrillation 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 Clinical Services Laboratory,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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
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 Health, Inc RCV000771119 SCV000902837 benign Arrhythmia 2018-03-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845517 SCV000987620 risk factor Left ventricular noncompaction criteria provided, single submitter clinical testing
Athena Diagnostics Inc 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 RCV001287425 SCV001474117 benign none provided 2020-01-16 criteria provided, single submitter clinical testing
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.

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