rs1060501127
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000335.5(SCN5A):c.5414_5417delCTCA(p.Thr1805SerfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000335.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5417_5420delCTCA | p.Thr1806SerfsTer27 | frameshift_variant | Exon 28 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.5414_5417delCTCA | p.Thr1805SerfsTer27 | frameshift_variant | Exon 28 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5417_5420delCTCA | p.Thr1806SerfsTer27 | frameshift_variant | Exon 28 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.5414_5417delCTCA | p.Thr1805SerfsTer27 | frameshift_variant | Exon 28 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
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 Pathogenic:1
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Thr1806Serfs*27) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 211 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with atrioventricular block (PMID: 22899775). ClinVar contains an entry for this variant (Variation ID: 406415). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs*10) have been determined to be pathogenic (PMID: 17897635, 18361072). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.5417_5420delCTCA variant, located in coding exon 27 of the SCN5A gene, results from a deletion of 4 nucleotides at nucleotide positions 5417 to 5420, causing a translational frameshift with a predicted alternate stop codon (p.T1806Sfs*27). This alteration has been reported in a subject with atrioventricular block and her similarly affected father (Baruteau AE et al. Circulation, 2012 Sep;126:1469-77). Frameshifts are typically deleterious in nature. Although this frameshift occurs at the 3' terminus of SCN5A and is not expected to trigger nonsense-mediated mRNA decay, it alters more than 10% of the protein. Based on the available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at