rs199473180

chr3-38581266-G-Achr3-38581266-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.2893C>T(p.Arg965Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,612,492 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:3 U:6 O:1
• Conservation: PhyloP100: 5.57

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 11 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 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 chr3-38581265-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2893C>T	p.Arg965Cys	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2893C>T	p.Arg965Cys	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2893C>T	p.Arg965Cys	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2893C>T	p.Arg965Cys	missense_variant	17/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000649 AC: 16 AN: 246378 Hom.: 0 AF XY: 0.0000972 AC XY: 13 AN XY: 133778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000560

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460234 Hom.: 0 Cov.: 36 AF XY: 0.0000289 AC XY: 21 AN XY: 726196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000661 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 965 of the SCN5A protein (p.Arg965Cys). This variant is present in population databases (rs199473180, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome, dilated cardiomyopathy, and long QT syndrome (PMID: 11901046, 23293604, 23321620, 24524602, 24762593, 30847666, 32619740, 33221895). ClinVar contains an entry for this variant (Variation ID: 67763). 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: 19272188, 33764691). 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 12, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. SCN5A: p.Arg965Cys (c.2893C>T). See in a family with Brugada syndrome in our center with segregation in an affected first degree relative. We currently (4/27/2012) classify it as likely disease causing, based on the data reviewed below. In total the variant has been seen in ~4 unrelated individuals with Brugada syndrome, not including the patient's family. Priori et al (2000, 2002) reported observing this variant in a 30yo male with Brugada Syndrome who received an appropriate shock while sleeping (Priori et al 2002). Ancestry was not reported, though the cohort was recruited in Europe. Hsueh et al (2009) observed p.Arg965Cys in an individual with Brugada syndrome from Taiwan who had a history of ventricular fibrillation arrest. The variant was listed as observed in three unrelated individuals in a multi-center published compendium of SCN5A variants (Kapplinger et al 2010). These three cases were contributed by the Brugada group, Paris, and PGxHealth (now Transgenomics). The case from the Brugada group may very well be the patient's family, while the other two cases are likely unique. No segregation data was provided in these reports, though we do have some weak segregation data in the patient's family with both the patient and his brother having this variant and phenotypic evidence of Brugada syndrome. GeneDx gave me a verbal update on 4/27/2012 that they have seen this variant in one other individual, a 5 year old Caucasian male tested with their long QT panel, but with diagnosis not reported. Variants affecting the same codon (p.Arg965His and p.Arg965Leu) and surrounding codons (p.Gln960Lys and p.Arg971Cys) have been reported in association with Brugada and LQT syndromes. The variant occurs in the interdomain cytoplasmic linkers DII-DIII. Hsueh et al (2009) studied the in vitro phenotype using patch clamp assays and reported that the steady state inactivation was shifted to a more negative potential with slower recovery from inactivation. This non-conservative amino acid substitution replaces a polar, positive Arginine codon with a neutral Cysteine. Polyphen2 predicts the variant to be probably damaging. The Arginine at codon 965 is conserved across species. In total, the variant has not been observed in ~7024 control or general population samples studied, with less than 100 of these samples matching the patient's Asian ancestry (though the majority of the samples match the ancestry of several of the reported cases). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5300 Caucasian and African American individuals (as of 4/27/2012). A different variant at the same codon (p.Arg965Gly) as observed in 1/3419 Caucasians and 0/1706 African-American individuals in this dataset. There is no variation at codon 965 in the 24 Asian individuals in the NIEHS EGP dataset (as of 4/27/2012). Priori et al (2002) did not observe it in 400 control individuals (likely European ancestry). The variant is not currently listed in dbSNP or 1000 genomes (4/27/2012). Hsueh et al (2009) did not report control data. Kapplinger et al (2010) note the variant was not observed in 1300 population controls of varying ancestries. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2017	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg965Cys variant in SCN5A has been reported in at least 11 individuals: 7 with Brugada s yndrome, 1 with arrhythmogenic right ventricular cardiomyopathy (ARVC) and 3 wit h long QT syndrome, one of whom also carried a variant in a different gene that may explain the long QT phenotype (Priori 2000, Priori 2002, Hsueh 2009, Kapplin ger 2010, Duthoit 2012, Lieve 2013, Sommariva 2013, Jimmy 2014, Mellor 2017). Ad ditionally, this variant reportedly segregated with disease in one affected rela tive (ClinVar: SCV000280471.1). In vitro functional studies provide some evidenc e that the p.Arg965Cys variant may impact protein function (Hsueh 2009). This va riant has also been identified in 10/17136 of East Asian chromosomes by gnomAD ( http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis suggest that the p.Arg965Cys variant may impact the protein. Additio nally, two other missense changes in this codon (p.Arg965His and p.Arg965Leu) ha ve been identified in patients with Brugada syndrome and/or Long QT syndrome, ra ising the possibility that changes at this position may not tolerated (Meregalli 2006, Kapplinger 2009 and 2010, Amin 2011, Hoshi 2014). However, the clinical s ignificance of these changes is uncertain. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of the p.Arg965Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PP3, PS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2022	Variant summary: SCN5A c.2893C>T (p.Arg965Cys) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 246378 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. It has also been reported as a common founder variant predosposing to Brugada syndrome in the Thai population (PMID 34092119). This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (6.5e-05 vs 0.00017), allowing no conclusion about variant significance. c.2893C>T has been reported in the literature among individuals with features of Brugada syndrome as well unaffected individuals /unaffected family members with a reported penetrance of approximately 35% (example, PMID 11901046, 11076825, 19272188, 20129283, 23293604, 23321620, 24762593, 23631430, 34092119). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hsueh_2009) reporting a sodium channel with impaired steady state inactivation and impaired recovery from inactivation and slow inactivation. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4, Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2023

The p.R965C variant (also known as c.2893C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 2893. The arginine at codon 965 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in Brugada syndrome and sudden death cohorts (Priori SG et al. Circulation, 2002 Mar;105:1342-7; Hsueh CH et al. J. Biomed. Sci., 2009 Feb;16:23; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10). Functional studies show this alteration may also have an affect on the sodium channel, though the clinical significance of the observed impact is unclear (Hsueh CH et al. J. Biomed. Sci., 2009 Feb;16:23). This alteration is also present in the general population at a frequency higher than expected for pathogenic SCN5A alterations. 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 conflicting 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 arginine with cysteine at codon 965 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). Functional studies have shown that this variant has no impact on peak current but may affect inactivation of the sodium channel in transfected cells (PMID: 19272188, 33764691). This variant has been reported in at least 17 unrelated individuals affected with Brugada syndrome, including 10 from Northern or Northeastern region of Thailand (PMID: 11076825, 11901046, 23293604, 23321620, 32268277, 32619740, 33071830, 34092119, 36303204). This variant has been reported in 3 individuals suspected of having Brugada syndrome (PMID: 20129283), 1 individual affected with sick sinus syndrome (PMID: 36927930), 1 individual affected with sudden cardiac death (PMID: 30670673), 1 individual suspected to be affected with epilepsy, 1 individual affected with other cardiovascular disease but not inherited arrhythmia (PMID: 31696929), and in 2 unaffected control individuals (PMID: 34092119). This variant has also been reported in a Chinese family affected with complex familial arrhythmia syndrome (PMID: 33764691). This variant occurred together with p.Arg1309His on the same chromosome in 6 affected and 2 unaffected individuals in this family. This variant has been identified in 16/246378 chromosomes (10/17864 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has shown a deleterious impact on SCN5A function through in vitro studies and has been observed in the control population as well as in affected individuals. 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. -

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:11076825;PMID:11901046;PMID:19272188;PMID:20129283). 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	Uncertain	0.55
CardioboostArm	Uncertain	0.35
CardioboostCm	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	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	0.78	T
PROVEAN	Pathogenic	-7.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
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		0.95
MutPred		0.97		Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);
MVP		0.95
MPC		0.26
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.88
gMVP		0.97

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: rs199473180; hg19: chr3-38622757; COSMIC: COSV61124032;