NM_001099404.2:c.280A>G
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001099404.2(SCN5A):c.280A>G(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000734 in 1,608,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 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. I94S) has been classified 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
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.280A>G | p.Ile94Val | missense_variant | Exon 3 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.280A>G | p.Ile94Val | missense_variant | Exon 3 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.280A>G | p.Ile94Val | missense_variant | Exon 3 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.280A>G | p.Ile94Val | missense_variant | Exon 3 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 249412 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.0000790 AC: 115AN: 1456018Hom.: 0 Cov.: 28 AF XY: 0.0000607 AC XY: 44AN XY: 724782 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25904541, 24613995) -
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the SCN5A protein (p.Ile94Val). This variant is present in population databases (rs202114798, gnomAD 0.007%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 24613995, 33500567, 34930020, 37652022). ClinVar contains an entry for this variant (Variation ID: 463314). 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:2
This missense variant replaces isoleucine with valine at codon 94 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of channel activity in cell culture (PMID: 24613995), while another in vitro study reported this variant does not change channel function (PMID: 34930020). This variant has been reported in an individual affected with irritable bowel syndrome who showed an Brugada-type ECG (PMID: 24613995), in an individual affected with left ventricular noncompaction (PMID: 33500567), and in three individuals affected with atrial fibrillation, long QT syndrome, and/or premature ventricular contraction (PMID: 34930020). This variant has been identified in 3/249412 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. -
This missense variant replaces isoleucine with valine at codon 94 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of channel activity in cell culture (PMID: 24613995), while another in vitro study reported this variant does not change channel function (PMID: 34930020). This variant has been reported in an individual affected with irritable bowel syndrome who showed an Brugada-type ECG (PMID: 24613995), in an individual affected with left ventricular noncompaction (PMID: 33500567), and in three individuals affected with atrial fibrillation, long QT syndrome, and/or premature ventricular contraction (PMID: 34930020). This variant has been identified in 3/249412 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. -
not specified Uncertain:1
The p.Ile94Val variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/9808 African chromosomes and 1 /16508 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs202114798). Computational prediction tools and conservation analysis suggest that the p.Ile94Val variant may not impact the pr otein, though this information is not predictive enough to rule out pathogenicit y. Of note, a different variant at this amino acid position (p.Ile94Ser) has bee n identified in 1 individual with Brugada Syndrome (Kapplinger 2010). In summary , the clinical significance of the p.Ile94Val variant is uncertain. -
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
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Long QT syndrome 3 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss of function or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however, SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301690). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by multiple clinical laboratories in ClinVar, and has been observed in individuals with dilated cardiomyopathy, long QT syndrome or irritable bowel syndrome (PMID: 34930020, 31983221, 24613995). (I) 1010 - Functional evidence for this variant is inconclusive. Patch clamp studies showed that this variant displayed similar properties to wild type on most measures except for a decrease in slope of the voltage dependence of inactivation (PMID: 24613995). (I) 1206 - This variant has been shown to be paternally inherited (by Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Cardiovascular phenotype Uncertain:1
The p.I94V variant (also known as c.280A>G), located in coding exon 2 of the SCN5A gene, results from an A to G substitution at nucleotide position 280. The isoleucine at codon 94 is replaced by valine, an amino acid with highly similar properties, and is located in the N-terminal, cytoplasmic region. This variant was detected in an individual from an irritable bowel syndrome cohort who was reported to have Brugada syndrome pattern on ECG, and in individuals with electronic health record indication of arrhythmia (Beyder A. Gastroenterology. 2014;146(7):1659-1668; Glazer AM et al. Circulation. 2022 03;145(12):877-891). This variant has also been detected in an individual from a control cohort (Kapplinger JD. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95). In vitro studies reported this variant to have peak current density similar to wild type, but some impact to other parameters of channel function (Beyder A. Gastroenterology. 2014;146(7):1659-1668; Glazer AM et al. Circulation. 2022 03;145(12):877-891). This amino acid position is well 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 alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at