NM_001099404.2:c.2878C>A
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001099404.2(SCN5A):c.2878C>A(p.Gln960Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,968 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 (★★).
Frequency
Consequence
NM_001099404.2 missense
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
Genome browser will be placed here
ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2878C>A | p.Gln960Lys | missense_variant | Exon 17 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.2878C>A | p.Gln960Lys | missense_variant | Exon 17 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2878C>A | p.Gln960Lys | missense_variant | Exon 17 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.2878C>A | p.Gln960Lys | missense_variant | Exon 17 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460796Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 726508 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322 show subpopulations
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 Uncertain:1
- -
not provided Uncertain:1
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 960 of the SCN5A protein (p.Gln960Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67762). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiac arrhythmia Uncertain:1
This missense variant replaces glutamine with lysine at codon 960 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 19716085, 25904541). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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