rs199473222
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_001099404.2(SCN5A):c.3976G>T(p.Ala1326Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1326D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3976G>T | p.Ala1326Ser | missense_variant | 23/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3973G>T | p.Ala1325Ser | missense_variant | 23/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3976G>T | p.Ala1326Ser | missense_variant | 23/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3973G>T | p.Ala1325Ser | missense_variant | 23/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2014 | p.Ala1326Ser (GCC>TCC): c.3976 G>T in exon 23 of the SCN5A gene (NM_198056.2) The A1326S mutation in the SCN5A gene has been reported in association with LQTS and was absent from at least 2,600 reference alleles (Kapplinger et al., 2009). A1326S results in a non-conservative amino acid substitution of Alanine at a position that is conserved across species. Mutations in nearby residues (V1323G, N1325S, A1330P, A1330T) have been reported in association with familial forms of arrhythmia, further supporting the functional importance of this region of the protein. Furthermore, the A1326S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, A1326S in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in ARRHYTHMIA panel(s). - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at