NM_001099404.2:c.2924G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001099404.2(SCN5A):c.2924G>A(p.Arg975Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,610,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R975W) 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.2924G>A | p.Arg975Gln | missense_variant | Exon 17 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.2924G>A | p.Arg975Gln | 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.2924G>A | p.Arg975Gln | missense_variant | Exon 17 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.2924G>A | p.Arg975Gln | missense_variant | Exon 17 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151738Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000372 AC: 9AN: 241948 AF XY: 0.0000380 show subpopulations
GnomAD4 exome AF: 0.0000541 AC: 79AN: 1459092Hom.: 0 Cov.: 36 AF XY: 0.0000524 AC XY: 38AN XY: 725586 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151738Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74058 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:5
SCN5A: PM2, BP4 -
Reported in association with sudden infant death syndrome (SIDS), sudden unexplained death (SUD), long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM); however, no specific clinical information or segregation studies were provided and additional cardiogenetic variants were identified in some cases (PMID: 31737537, 29517769, 30847666, 37614113, Osawa. (2011) Forensic Science International: Genetics Supplement Series. 3 (1):e263 - e264); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 29517769, 26746457, 31737537, 35982159, 37614113, 36973604, 33057194) -
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This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 975 of the SCN5A protein (p.Arg975Gln). This variant is present in population databases (rs753149586, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 201483). 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. -
Long QT syndrome 3 Uncertain:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiac arrhythmia Uncertain:2
This missense variant replaces arginine with glutamine at codon 975 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant affected with sudden death (Osawa et al, 2011) and in individuals with dilated cardiomyopathy (PMID: 29517769), arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666), suspected long QT syndrome (PMID: 31737537), and ischemic stroke (PMID: 36973604). This variant has been identified in 11/273312 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 arginine with glutamine at codon 975 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant affected with sudden death (Osawa et al, 2011) and in individuals with dilated cardiomyopathy (PMID: 29517769), arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666), suspected long QT syndrome (PMID: 31737537), and ischemic stroke (PMID: 36973604). This variant has been identified in 11/273312 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
Variant summary: SCN5A c.2924G>A (p.Arg975Gln) results in a conservative amino acid change located in the sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 241948 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2924G>A has been reported in the literature in individuals affected with cardiomyopathies, stroke, and developmental disorders (e.g., Kaplanis_2020, Marschall_2019, Rohrer_2023, VanDriest_2016, VanLint_2019, Alkhamis_2023, Herkert_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33057194, 31737537, 37614113, 26746457, 30847666, 36973604, 29517769). ClinVar contains an entry for this variant (Variation ID: 201483). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Brugada syndrome 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Dilated cardiomyopathy 1E Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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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Sick sinus syndrome 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Progressive familial heart block, type 1A Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiovascular phenotype Uncertain:1
The p.R975Q variant (also known as c.2924G>A), located in coding exon 16 of the SCN5A gene, results from a G to A substitution at nucleotide position 2924. The arginine at codon 975 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in a sudden infant death case with no clinical details and in a dilated cardiomyopathy case with additional variants detected (Osawa M et al., Forens Sci Intl: Supp 3, 2011: e263-e264; Herkert JC et al. Genet. Med., 2018 11;20:1374-1386). This variant was also detected in genetic testing cohorts; 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; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is not 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