3-38550679-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5
The NM_000335.5(SCN5A):c.5690G>A(p.Arg1897His) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
6
9
5
Clinical Significance
Conservation
PhyloP100: 6.15
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a region_of_interest Interaction with FGF13 (size 62) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
PP5
Variant 3-38550679-C-T is Pathogenic according to our data. Variant chr3-38550679-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207974.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=6}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5693G>A | p.Arg1898His | missense_variant | 28/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.5690G>A | p.Arg1897His | missense_variant | 28/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5693G>A | p.Arg1898His | missense_variant | 28/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.5690G>A | p.Arg1897His | missense_variant | 28/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249288Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135230
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461672Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727114
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1898 of the SCN5A protein (p.Arg1898His). This variant is present in population databases (rs370694515, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and/or long QT Syndrome (PMID: 25163546, 28069705, 34755423, 36303204). This variant is also known as c.G5639A, p.R1880H. ClinVar contains an entry for this variant (Variation ID: 207974). 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: 28069705). This variant disrupts the p.Arg1898 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 26173111), which suggests that this may be a clinically significant amino acid residue. 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 | Oct 17, 2019 | Identified in a patient with DCM and a patient with clinical features suggestive of ARVC in the published literature (Haas et al., 2015; Te Riele et al., 2017); Functional studies in patient derived cells suggest this variant leads to a reduction in both peak sodium current and channel clusters at intercalated discs (Te Riele et al., 2017). However, further functional studies are needed to clarify the role of this variant in human disease.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID 207974; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25904541, 31336969, 28069705, 25163546, 29845439, 30205876, 30302938) - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with histidine at codon 1898 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant reduces sodium current and may disrupt formation of a functional complex with cell adhesion molecules (PMID: 28069705). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 25163546), arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and flu myocarditis (PMID: 30084490). This variant has also been identified in 12/280694 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 01, 2023 | This missense variant replaces arginine with histidine at codon 1898 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant reduces sodium current and may disrupt formation of a functional complex with cell adhesion molecules (PMID: 28069705). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 25163546), arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and flu myocarditis (PMID: 30084490). This variant has also been identified in 12/280694 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. - |
Long QT syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 01, 2014 | - - |
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 06, 2019 | The p.Arg1898His variant in SCN5A has been reported in one patient with DCM (Haas 2015) and in one patient with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Te Riele 2017) and also in 1 individual with left ventricular non compaction with segmental hypertrophy (LMM data). It is also present in ClinVar (ID 207974). It has been identified in 7/30602 South Asian chromosomes by the gnomAD. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1898His variant is uncertain. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2023 | The p.R1898H variant (also known as c.5693G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5693. The arginine at codon 1898 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a dilated cardiomyopathy cohort, in an individual with confirmed myocarditis, and an individual with features of arrhythmogenic right ventricular cardiomyopathy (Haas J et al. Eur. Heart J., 2015;36:1123-35a; Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111; Nelson McMillan K. Artif Organs. 2019;43(1):21-29). This variant (referred to as p.R1865H) co-occurred with a de novo KCNH2 variant in an individual with overlapped phenotypes of LQTS and sinoatrial node dysfunction, while two reportedly unaffected relatives also had this SCN5A variant (Yang Z et al. Ann Noninvasive Electrocardiol. 2022 Jan;27(1):e12889). This variant has also been detected in a self-reported healthy cohort; however, details were limited (Bajaj A et al. Hum Genomics. 2022 Aug;16(1):30). One study indicated this alteration may have an impact on sodium channel function (Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D;D;T;D;D;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
P;B;.;P;.;D;D;.;.
Vest4
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at