chr3-38603950-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2PM5PP2BP4_Strong
The NM_000335.5(SCN5A):c.1652C>T(p.Ala551Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A551T) has been classified as Pathogenic.
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1652C>T | p.Ala551Val | missense_variant | 12/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.1652C>T | p.Ala551Val | missense_variant | 12/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1652C>T | p.Ala551Val | missense_variant | 12/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.1652C>T | p.Ala551Val | missense_variant | 12/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249006Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135130
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727116
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74480
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This missense variant replaces alanine with valine at codon 551 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). A functional study has shown that this variant may affect inactivation kinetics of the sodium channel (PMID: 19706159). This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 11/280390 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 | Color Diagnostics, LLC DBA Color Health | Dec 19, 2022 | This missense variant replaces alanine with valine at codon 551 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). A functional study has shown that this variant may affect inactivation kinetics of the sodium channel (PMID: 19706159). This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 11/280390 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. - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 551 of the SCN5A protein (p.Ala551Val). This variant is present in population databases (rs201641342, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 191381). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 19706159). 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. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2023 | The p.A551V variant (also known as c.1652C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1652. The alanine at codon 551 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort, as well as in a control population of a study cohort (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). Additionally, in vitro analysis showed this alteration may impact protein function (Chiang KC et al. J Biomed Sci, 2009 Aug;16:76). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at