rs199473168

Positions:

• chr3-38585846-G-A

Variant summary

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

The ENST00000423572.7(SCN5A):​c.2632C>T​(p.Arg878Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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. R878H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A ENST00000423572.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 10.0

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 repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 72 pathogenic changes around while only 4 benign (95%) in ENST00000423572.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38585845-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67745.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1, not_provided=1}.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 3-38585846-G-A is Pathogenic according to our data. Variant chr3-38585846-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38585846-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2632C>T	p.Arg878Cys	missense_variant	16/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2632C>T	p.Arg878Cys	missense_variant	16/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2632C>T	p.Arg878Cys	missense_variant	16/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.2632C>T	p.Arg878Cys	missense_variant	16/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 878 of the SCN5A protein (p.Arg878Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 18616619, 20960618, 26036855, 28341781, 28781330). ClinVar contains an entry for this variant (Variation ID: 67744). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 18616619, 20384651, 20539757, 22739120). This variant disrupts the p.Arg878 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 25904541, 30193851; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	Reported to segregate with varying arrhythmia phenotypes in four individuals from one family (Zhang et al., 2008); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 67744; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22840528, 28449774, 18616619, 20539757, 27381756, 20960617, 24136861, 17368591, 25399282, 26036855, 30476647, 29233994, 30232268, 22739120, 28781330, 28341781, 20129283, 24055942, 30662450, 33131149) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2018

The p.R878C variant (also known as c.2632C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2632. The arginine at codon 878 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with Brugada syndrome and sick sinus syndrome (Savastano S et al. Heart Rhythm, 2014 Jul;11:1176-83; Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Crotti L et al. J. Am. Coll. Cardiol., 2012 Oct;60:1410-8; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). Segregation with disease has been reported in some families; however, clinical information was limited and some family members had additional variants (Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23; Bissay V et al. Eur. J. Hum. Genet., 2016 Mar;24:400-7; Van Malderen SCH et al. Circ. J., 2017 Dec;82:53-61). This variant is located in the S5-S6 pore-forming segment of the DII domain, and functional studies have demonstrated loss of sodium channel function despite proper localization in the cell membrane (Gui J et al. PLoS ONE, 2010 Jun;5:e10985; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Brugada syndrome 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 Brugada syndrome in the following publications (PMID:18616619;PMID:20129283;PMID:20539757;PMID:20960617). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	.;H;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.94
MutPred		0.91		Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);Gain of catalytic residue at W879 (P = 0.0082);
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.98

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: rs199473168; hg19: chr3-38627337; COSMIC: COSV61137951;