3-38605956-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000335.5(SCN5A):c.1333C>G(p.His445Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,604,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H445H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
3
11
6
Clinical Significance
Conservation
PhyloP100: 6.68
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 Uncertain_significance. Variant got 3 ACMG points.
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). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the 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.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1333C>G | p.His445Asp | missense_variant | 10/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.1333C>G | p.His445Asp | missense_variant | 10/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000533 AC: 13AN: 243840Hom.: 0 AF XY: 0.0000378 AC XY: 5AN XY: 132114
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GnomAD4 exome AF: 0.000129 AC: 188AN: 1452388Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 81AN XY: 721306
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74482
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 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) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (17 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated DI to DII intracellular linker domain (UniProt). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(His445Gln) and p.(His445Tyr) variants have each been reported once as a VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has previously been reported in individuals with Brugada syndrome, atrial fibrillation, and sudden infant death syndrome (SIDS), and has been classified as both a VUS and potentially disease causing (PMID: 30193851, PMID: 25650408, PMID: 18378609, PMID: 30086531, ClinVar). (I) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with atrial fibrillation in a proband and two affected family members. Additionally, the variant was absent from an unaffected family member (PMID: 18378609). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 26, 2024 | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 445 of the SCN5A protein (p.His445Asp). This variant is present in population databases (rs199473112, gnomAD 0.008%). This missense change has been observed in individual(s) with Brugada syndrome, dilated cardiomyopathy, or atrial fibrillation (PMID: 18378609, 19808477, 25650408, 30193851, 37652022). ClinVar contains an entry for this variant (Variation ID: 30046). 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. This variant disrupts the p.His445 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (internal data), 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 | Feb 26, 2020 | Identified in patients with LQTS, atrial fibrillation, Brugada syndrome, or sudden infant death either tested at GeneDx or in the published literature (Darbar et al., 2008; Le Scouarnec et al., 2015; Campuzano et al., 2018); however, some individuals harbor additional variants that could explain their phenotype; Observed to segregate with atrial fibrillation in one proband's affected father and brother (Darbar et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30046; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19808477, 22581653, 25650408, 18378609, 28150151, 30086531, 28086167, 30193851) - |
Atrial fibrillation, familial, 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 15, 2008 | - - |
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 | Feb 14, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2024 | The p.H445D variant (also known as c.1333C>G), located in coding exon 9 of the SCN5A gene, results from a C to G substitution at nucleotide position 1333. The histidine at codon 445 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in individuals from various cohorts including sudden infant death, sudden death, arrhythmia, and Brugada syndrome; however, clinical details were limited, some reports may overlap, and additional variants in were also detected in some cases (Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63; Campuzano O et al. Forensic Sci Int, 2017 Feb;271:120-125; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant has also been reported in association with atrial fibrillation and, in one family, was detected in three affected individuals (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). This amino acid position is not well 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. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 15, 2023 | This missense variant replaces histidine with aspartic acid at codon 445 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 voltage-dependence of activation, recovery and inactivation of the sodium channel (Gillani et al., 2010). This variant has been reported in individuals affected with atrial fibrillation (PMID: 18378609, 19808477), Brugada syndrome (PMID: 25650408, 30193851, 32893267), dilated cardiomyopathy (PMID: 32826072), and sudden death in infancy (PMID: 30086531). This variant has also been identified in 14/275240 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. - |
Atrial fibrillation Other:1
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 Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;N;.;.;.;N;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;B;.;B;.;B;B;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);
MVP
MPC
0.61
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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