3-38579416-G-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BA1
The NM_000335.5(SCN5A):c.3305C>A(p.Ser1102Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,612,416 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.3308C>A | p.Ser1103Tyr | missense_variant | Exon 18 of 28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.3305C>A | p.Ser1102Tyr | missense_variant | Exon 18 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.3308C>A | p.Ser1103Tyr | missense_variant | Exon 18 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.3305C>A | p.Ser1102Tyr | missense_variant | Exon 18 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.0226 AC: 3436AN: 152190Hom.: 154 Cov.: 33
GnomAD3 exomes AF: 0.00586 AC: 1441AN: 246002Hom.: 57 AF XY: 0.00461 AC XY: 619AN XY: 134128
GnomAD4 exome AF: 0.00245 AC: 3580AN: 1460108Hom.: 134 Cov.: 31 AF XY: 0.00216 AC XY: 1568AN XY: 726266
GnomAD4 genome 0.0226 AC: 3435AN: 152308Hom.: 154 Cov.: 33 AF XY: 0.0216 AC XY: 1608AN XY: 74458
ClinVar
Submissions by phenotype
not provided Benign:5Other:1
This variant has been reported in the following publications (PMID:12193783;PMID:15161528;PMID:19841300;PMID:20129283). -
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This variant is associated with the following publications: (PMID: 24332150, 21325150, 21498565, 24951663, 16061744, 20129283, 15851227, 15992732, 18452875, 16453024, 21385947, 12193783, 31019283, 31043699, 32880476) -
not specified Uncertain:1Benign:4
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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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. -
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 -
Brugada syndrome Uncertain:1Benign:1
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Risk factor for disease development: PS3_mod;PS4_mod;PP2;BS1;BS2;BP4;BP6 -
Dilated cardiomyopathy 1E Uncertain:1Benign:1
A heterozygous SCN5A c.3305C>A (p.Ser1102Tyr) variant (alternatively referred to as p.Ser1103Tyr in the literature) was identified. This variant is commonly observed in the African-American population with a minor allele frequency of 8.1%, with many homozygotes reported (gnomAD database). The incidence of this variant is too high to be consistent with it being a cause of high-penetrance monogenic disease. However, some studies have reported an over-representation of the SCN5A c.3305C>A (p.Ser1102Tyr) allele in cohorts under study for cardiac arrhythmia and sudden infant death syndrome (SIDS) (Splawski I et al., PMID: 12193783, Van Norstrand DW et al., PMID: 18452875, Plant LD et al., PMID: 16453024). Adjusted for age and sex, the relative risk of an unexplained arrhythmic death was 8.4 (95% CI 2.1 to 28.6, P=0.001) with the Y1102 allele compared with noncardiac deaths. The relative risk for cardiac arrhythmias with mild cardiac hypertrophy was 4.9 (95% CI 1.3 to 13.4, P=0.01) (Burke A et al., PMID: 16061744). Based on available information and the ClinGen Low Penetrance/Risk Allele Working Group recommendations (Schmidt RJ et al., PMID: 38054408) this variant is classified as an uncertain risk allele. -
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. -
Long QT syndrome 3 Benign:2
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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. -
Cardiac arrhythmia Benign:2
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SUDDEN INFANT DEATH SYNDROME Pathogenic:1
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Brugada syndrome 1 Benign:1
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. -
Ventricular fibrillation, paroxysmal familial, type 1 Benign:1
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. -
Cardiomyopathy Benign:1
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SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Benign:1
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Congenital long QT syndrome Benign:1
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Sick sinus syndrome 1 Benign:1
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. -
Progressive familial heart block, type 1A Benign:1
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. -
Primary dilated cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
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. -
Long QT syndrome 3, acquired, susceptibility to Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at