3-38630420-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_001099404.2(SCN5A):c.283G>A(p.Val95Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,608,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.283G>A | p.Val95Ile | missense_variant | 3/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.283G>A | p.Val95Ile | missense_variant | 3/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.283G>A | p.Val95Ile | missense_variant | 3/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.283G>A | p.Val95Ile | missense_variant | 3/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249414Hom.: 1 AF XY: 0.00 AC XY: 0AN XY: 135290
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1456324Hom.: 1 Cov.: 28 AF XY: 0.00000552 AC XY: 4AN XY: 724920
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74456
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces valine with isoleucine at codon 95 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). An experimental functional study has shown that this variant does not change sodium channel function in vitro (PMID: 23805106). This variant has been identified in an individual affected with Brugada syndrome (PMID: 17081365, 20877689), in an individual affected with sudden death (PMID: 24529773), and in another individual affected with left ventricular noncompaction (PMID: 33500567). This variant has been identified in 7/249414 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 26, 2023 | This missense variant replaces valine with isoleucine at codon 95 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). An experimental functional study has shown that this variant does not change sodium channel function in vitro (PMID: 23805106). This variant has been identified in an individual affected with Brugada syndrome (PMID: 17081365, 20877689), in an individual affected with sudden death (PMID: 24529773), and in another individual affected with left ventricular noncompaction (PMID: 33500567). This variant has been identified in 7/249414 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. - |
Brugada syndrome Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 95 of the SCN5A protein (p.Val95Ile). This variant is present in population databases (rs199473054, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome or left ventricular noncompaction cardiomyopathy (PMID: 20877689, 31397097, 33500567). ClinVar contains an entry for this variant (Variation ID: 67761). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 23805106). 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. - |
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:17081365;PMID:20877689). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2013 | p.Val95Ile (GTA>ATA): c.283 G>A in exon 3 of the SCN5A gene (NM_198056.2) The Val95Ile variant in the SCN5A gene has been reported previously in one Chinese individual diagnosed with Brugada syndrome, who also harbored the Ala1649Val variant in SCN5A (Liang P et al., 2006). Both variants were inherited from this patient's father who was asymptomatic and had a normal ECG, however, suggesting that V95I may not be pathogenic (Liang P et al., 2006). Additionally, Val95Ile was reported in one individual from a cohort of 120 sudden adult death cases in the Han Chinese (Hou Y et al., 2013). Mutations in nearby residues (Phe93Ser, Ile94Ser, Arg104Gln) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Val95Ile variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, one in vitro functional study showed that this variant does not affect sodium channel function (Gutter C et al., 2013). In summary, Val95Ile is a good candidate for a disease-causing mutation. The variant is found in ARRHYTHMIA panel(s). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 3 papers in HGMD, classified as DM related to Brugada syndrome. It has been seen in affected and unaffected patients. It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (in 2013). - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at