chr3-38585944-AC-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001099404.2(SCN5A):c.2533delG(p.Val845CysfsTer2) 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001099404.2 frameshift
Scores
Clinical Significance
Conservation
Publications
- Brugada syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Brugada syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1EInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- familial long QT syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- long QT syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- sick sinus syndrome 1Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- progressive familial heart block, type 1AInheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
- atrial standstillInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial atrial fibrillationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial sick sinus syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- paroxysmal familial ventricular fibrillationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- progressive familial heart blockInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- catecholaminergic polymorphic ventricular tachycardiaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- short QT syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2533delG | p.Val845CysfsTer2 | frameshift_variant | Exon 16 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.2533delG | p.Val845CysfsTer2 | frameshift_variant | Exon 16 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2533delG | p.Val845CysfsTer2 | frameshift_variant | Exon 16 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.2533delG | p.Val845CysfsTer2 | frameshift_variant | Exon 16 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Brugada syndrome Pathogenic:3
This variant deletes 1 nucleotide in exon 16 of the SCN5A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with Brugada syndrome (PMID: 20129283). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
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The p.Val845fs variant in SCN5A has been reported in 1 individual with suspected Brugada syndrome (Kapplinger 2010) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 201559). It was absent from large popula tion studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 845 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Loss of function variants in SCN5A are typically associated with Brugada syndrome although overlapping presentations in cluding other SCN5A related phenotypes (Long QT syndrome) have been described (R emme 2013). In summary, although additional studies are required to fully establ ish its clinical significance, the p.Val845fs variant is likely pathogenic. ACMG /AMP Criteria applied: PVS1, PM2 (Richards 2015). -
not provided Pathogenic:2
Reported in patients with Brugada syndrome or a prolonged QTc (PMID: 20129283, 32009526, 34649698); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20129283, 30662450, 31447099, 34649698, 32009526) -
This sequence change creates a premature translational stop signal (p.Val845Cysfs*2) 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 (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 201559). For these reasons, this variant has been classified as Pathogenic. -
Brugada syndrome 1 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The c.2533delG pathogenic mutation, located in coding exon 15 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 2533, causing a translational frameshift with a predicted alternate stop codon (p.V845Cfs*2). This alteration has been detected in multiple individuals with confirmed or suspected Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -
Cardiac arrhythmia Pathogenic:1
This variant deletes 1 nucleotide in exon 16 of the SCN5A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with Brugada syndrome (PMID: 20129283). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at