3-38579439-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000335.5(SCN5A):c.3282G>A(p.Trp1094*) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000335.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3285G>A | p.Trp1095* | stop_gained | Exon 18 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.3282G>A | p.Trp1094* | stop_gained | Exon 18 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Trp1095*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and epilepsy (PMID: 19561025, 23538271). ClinVar contains an entry for this variant (Variation ID: 406434). For these reasons, this variant has been classified as Pathogenic. -
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Brugada syndrome 1 Pathogenic:1
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Brugada syndrome Pathogenic:1
The p.Trp1095X variant in SCN5A has been reported in 1 individual with Brugada s yndrome (Yamagata 2017), and was absent from large population studies. The same amino acid change resulting from a different variant (c.3284 G>A) has been repor ted in another proband with Brugada syndrome and segregated with disease in 2 af fected relatives (Parisi 2013). The p.Trp1095X variant has also been reported in ClinVar (Variation ID 406434). This nonsense variant leads to a premature termi nation codon at position 1095, which is predicted to lead to a truncated or abse nt protein. Heterozygous loss of function of the SCN5A gene is an established di sease mechanism in Brugada syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp1095X variant i s likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2. -
Cardiovascular phenotype Pathogenic:1
The p.W1095* pathogenic mutation (also known as c.3285G>A), located in coding exon 17 of the SCN5A gene, results from a G to A substitution at nucleotide position 3285. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This variant has been detected in individuals with Brugada syndrome, and segregated with disease in one family with both Brugada syndrome and epilepsy (Catalano O et al. Eur Heart J, 2009 Sep;30:2241-8; Parisi P et al. Epilepsy Res, 2013 Aug;105:415-8; Yamagata K et al. Circulation, 2017 Jun;135:2255-2270). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at