rs199473282
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):c.4859C>T(p.Thr1620Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1620K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4859C>T | p.Thr1620Met | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4856C>T | p.Thr1619Met | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4859C>T | p.Thr1620Met | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4856C>T | p.Thr1619Met | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152020Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250918Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135682
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461708Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727136
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152020Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74246
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). This variant is present in population databases (rs199473282, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome and/or clinical features of SCN5A-related conditions (PMID: 9521325, 15520322, 20129283, 23785128, 29728395, 30847666, 34076677). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67932). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2022 | Multiple studies have examined the functional effect of the T1620M variant, with the general conclusion that this variant impacts sodium ion channel function (Chen et al., 1998; Dumaine et al., 1999; Makita et al., 2000; Shirai et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11786529, 11827685, 10618304, 11013131, 23785128, 29728395, 30662450, 30847666, 15520322, 20129283, 10532948, 11029409, 11123251, 9521325, 34135346, 33131149) - |
Brugada syndrome 1 Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Jun 15, 2022 | reported as secondary finding - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 01, 2021 | - - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 28, 2021 | This missense variant replaces threonine with methionine at codon 1620 in the transmembrane domain DIV of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541) and has been shown to segregate with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
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:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). 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