rs756474485
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001099404.2(SCN5A):c.1993G>T(p.Ala665Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
2
7
11
Clinical Significance
Conservation
PhyloP100: 4.11
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.34351042).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1993G>T | p.Ala665Ser | missense_variant | 13/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.1993G>T | p.Ala665Ser | missense_variant | 13/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1993G>T | p.Ala665Ser | missense_variant | 13/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
SCN5A | ENST00000423572.7 | c.1993G>T | p.Ala665Ser | missense_variant | 13/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000522 AC: 13AN: 249002Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135014
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461572Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727070
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2022 | 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) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 11, 2020 | - - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | 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. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 15, 2023 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 30, 2014 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;M;.;.;.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
D;T;D;D;T;D;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
P;D;.;P;.;B;D;.;.
Vest4
MutPred
Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);
MVP
MPC
0.97
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at