rs777061524
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001099404.2(SCN5A):c.1889C>T(p.Thr630Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,508,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T630K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1889C>T | p.Thr630Met | missense_variant, splice_region_variant | 12/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1889C>T | p.Thr630Met | missense_variant, splice_region_variant | 12/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1889C>T | p.Thr630Met | missense_variant, splice_region_variant | 12/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1889C>T | p.Thr630Met | missense_variant, splice_region_variant | 12/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000743 AC: 13AN: 175076Hom.: 0 AF XY: 0.0000540 AC XY: 5AN XY: 92586
GnomAD4 exome AF: 0.0000715 AC: 97AN: 1356226Hom.: 0 Cov.: 30 AF XY: 0.0000574 AC XY: 38AN XY: 662148
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 630 of the SCN5A protein (p.Thr630Met). This variant is present in population databases (rs777061524, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201462). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24613995). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | Reported in an individual with Brugada syndrome who harbored additional variants in the SCN5A and AKAP9 genes (PMID: 30847666); Identified in an individual with irritable bowel syndrome (IBS); however, no cardiac arrhythmia phenotype was reported (PMID: 24613995); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies suggest that this missense change may affect the channel function; however, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 24613995); This variant is associated with the following publications: (PMID: 25898860, 24613995, 30847666) - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 20, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2024 | The p.T630M variant (also known as c.1889C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1889. The threonine at codon 630 is replaced by methionine, an amino acid with similar properties. This variant was reported in an individual from a cohort of patients with irritable bowel syndrome being assessed for variants in SCN5A, and via an in vitro voltage clamp analysis, resulted in loss of function through faster inactivation of the Nav1.5 channel compared to wild type (Beyder A et al. Gastroenterology 2014;146(7):1659-68). This variant was also detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has also been reported in association with Brugada syndrome (Chen GX et al. EBioMedicine, 2023 Jan;87:104388). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2023 | This missense variant replaces threonine with methionine at codon 630 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant alters inactivation kinetics of the sodium channel (PMID: 24613995). This variant has been reported in an individual affected with Brugada syndrome (PMID: 30847666). This variant has been identified in 14/206444 chromosomes 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at