rs199473083

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):​c.845G>A​(p.Arg282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

8
9
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:2

Conservation

PhyloP100: 1.72
Variant links:
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 Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38609824-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
PP5
Variant 3-38609823-C-T is Pathogenic according to our data. Variant chr3-38609823-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38609823-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.845G>A p.Arg282His missense_variant Exon 7 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.845G>A p.Arg282His missense_variant Exon 7 of 28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkc.845G>A p.Arg282His missense_variant Exon 7 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.845G>A p.Arg282His missense_variant Exon 7 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249398
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135288
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461618
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Jun 09, 2021
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His). This variant is present in population databases (rs199473083, gnomAD 0.006%). This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68048). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). For these reasons, this variant has been classified as Pathogenic. -

Nov 27, 2020
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 11901046, 29574140, 36204818, 36516610, 33131149, 30203441, 31440721, 35305865, 16864729) -

Oct 02, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Brugada syndrome Pathogenic:1Other:1
Sep 27, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 282 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

-
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype Pathogenic:1
Jan 20, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cardiac arrhythmia Pathogenic:1
Dec 05, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1 Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
CardioboostCm
Uncertain
0.16
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.5
.;L;.;.;.;L;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.5
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0090
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;D;D;.;.
Vest4
0.87
MutPred
0.89
Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);
MVP
0.96
MPC
1.3
ClinPred
0.89
D
GERP RS
5.3
Varity_R
0.46
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473083; hg19: chr3-38651314; COSMIC: COSV61118240; COSMIC: COSV61118240; API