rs199473110
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.1237G>T(p.Ala413Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,628 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A413E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1237G>T | p.Ala413Ser | missense_variant | 10/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1237G>T | p.Ala413Ser | missense_variant | 10/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1237G>T | p.Ala413Ser | missense_variant | 10/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1237G>T | p.Ala413Ser | missense_variant | 10/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461628Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727106
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 13, 2015 | The p.Ala413Ser variant in SCN5A has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis do not provide strong evidence for or against an i mpact the protein. In summary, the clinical significance of the p.Ala413Ser vari ant is uncertain. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2022 | The p.A413S variant (also known as c.1237G>T), located in coding exon 9 of the SCN5A gene, results from a G to T substitution at nucleotide position 1237. The alanine at codon 413 is replaced by serine, an amino acid with similar properties. This alteration has been reported in an epilepsy cohort with limited clinical details, as well as a pediatric cardiomyopathy cohort in an individual with limited clinical details and additional alterations in other cardiac-related genes (Li X et al. Ann Hum Genet, 2020 03;84:161-168; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at