rs370588133
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.4070C>T(p.Ala1357Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1357A) has been classified as Likely benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4070C>T | p.Ala1357Val | missense_variant | 23/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4067C>T | p.Ala1356Val | missense_variant | 23/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4070C>T | p.Ala1357Val | missense_variant | 23/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4067C>T | p.Ala1356Val | missense_variant | 23/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251474Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135910
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727246
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Likely pathogenic, flagged submission | clinical testing | GeneDx | May 05, 2014 | The A1357V variant that is likely pathogenic in the SCN5A gene has been reported previously in one patient with LQTS, and was not reported in at least 600 control alleles (Lieve K et al., 2013). The A1357V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, missense mutations in nearby residues (M1351R, V1353M G1358W, K1359N) have been reported in association with Brugada, supporting the functional importance of this region of the protein. Nevertheless, the A1357V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in CARDIOMYOPATHY panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the SCN5A protein (p.Ala1357Val). This variant is present in population databases (rs370588133, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 30193851). ClinVar contains an entry for this variant (Variation ID: 201505). 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 disruptive. 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 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 17, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2022 | The p.A1357V variant (also known as c.4070C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4070. The alanine at codon 1357 is replaced by valine, an amino acid with similar properties, and is located in the DIII/S5 region of the protein. This alteration was reported in an individual with suspected diagnosis of long QT syndrome; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This alteration has also been seen in an exome cohort and in one ostensibly healthy individual (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 27, 2023 | This missense variant replaces alanine with valine at codon 1357 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 30193851, 32893267), in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35663620), and in an individual suspected of having long QT syndrome testing (PMID: 23631430). This variant has also been identified in 19/282878 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at