rs199473083

chr3-38609823-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(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 Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 3) in uniprot entity SCN5A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68047.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, not_provided=1, Likely_pathogenic=3}.
• PP2: Missense variant where missense usually causes diseases, SCN5A
• 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/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.845G>A	p.Arg282His	missense_variant	7/28	ENST00000413689.6
SCN5A	NM_000335.5	c.845G>A	p.Arg282His	missense_variant	7/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.845G>A	p.Arg282His	missense_variant	7/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.845G>A	p.Arg282His	missense_variant	7/28	1	NM_000335.5	A1

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

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

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:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2023	ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. This variant is present in population databases (rs199473083, gnomAD 0.006%). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (Itoh et al., 2005; Poelzing et al., 2006; Shinlapawittayatorn et al., 2011); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 11901046, 29574140, 33131149, 30203441, 31440721, 16864729) -

Brugada syndrome Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	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. -
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 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

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

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostArm	Benign	0.013
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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

Other links and lift over

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