rs199473096
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):c.1058C>T(p.Thr353Ile) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T353S) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1058C>T | p.Thr353Ile | missense_variant | 9/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1058C>T | p.Thr353Ile | missense_variant | 9/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1058C>T | p.Thr353Ile | missense_variant | 9/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1058C>T | p.Thr353Ile | missense_variant | 9/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects SCN5A protein function (PMID: 17198989, 25261036). This variant has been observed in individual(s) with Brugada syndrome (PMID: 17198989). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67631). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 353 of the SCN5A protein (p.Thr353Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 29, 2023 | PP1_moderate, PP3, PM1, PM2_supporting, PS3_moderate, PS4_moderate - |
Brugada 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 Brugada syndrome in the following publications (PMID:17198989). 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