rs137854614

Positions:

• chr3-38550988-T-C

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.5384A>G​(p.Tyr1795Cys) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1795H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.01

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain 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 chr3-38550989-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9397.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 4.7729 (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, 0.977
• PP5: Variant 3-38550988-T-C is Pathogenic according to our data. Variant chr3-38550988-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550988-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5384A>G	p.Tyr1795Cys	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5381A>G	p.Tyr1794Cys	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5384A>G	p.Tyr1795Cys	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5381A>G	p.Tyr1794Cys	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 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	Mar 03, 2018	This sequence change replaces tyrosine with cysteine at codon 1795 of the SCN5A protein (p.Tyr1795Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with long QT syndrome in two families (PMID: 11410597, 18929331) and has been reported in an individual with this condition (PMID: 22129298). ClinVar contains an entry for this variant (Variation ID: 9375). Experimental studies have shown that this missense change disrupts SCN5A channel function causing a sustained inward sodium channel current and slowing the onset of inactivation with a prolongation of the action potential (PMID: 11410597, 14990510, 16254012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 9375; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have shown that Y1795C results in delayed sodium channel inactivation compared to wild type, delaying repolarization and prolonging the QT interval (Rivolta et al., 2001; Clancy et al., 2002; Tateyama et al., 2004; Berecki et al., 2006; Vecchietti et al., 2007); This variant is associated with the following publications: (PMID: 32161207, 28087622, 30361497, 30497731, 28213505, 31257342, 25460862, 24903439, 25904541, 18929331, 12417563, 16254012, 11410597, 24667783, 12084774, 16980337, 14990510, 22129298, 31865383, 19716085) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2017

The p.Y1795C pathogenic mutation (also known as c.5384A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 5384. The tyrosine at codon 1795 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals with long QT syndrome type 3 (LQT3), with segregation reported in multiple families (Rivolta I et al. J. Biol. Chem., 2001 Aug;276:30623-30; Vecchietti S et al. Am. J. Physiol. Heart Circ. Physiol., 2007 Jan;292:H56-65; Benito B et al. Heart Rhythm, 2008 Oct;5:1434-40; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Kilinc OU et al. Congenit Heart Dis 2012 Nov;7:E42-5). In addition, functional studies have demonstrated this alteration leads to slowed inactivation and prolonged depolarization in sodium channels (Rivolta I et al. J. Biol. Chem., 2001 Aug;276:30623-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Long QT syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 17, 2001

- -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:11410597;PMID:15840476;PMID:19716085;PMID:19841300;PMID:18929331). 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	0.93
CardioboostCm	Uncertain	0.72
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.3	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		0.79
MutPred		0.86		.;.;Gain of catalytic residue at M1793 (P = 9e-04);.;.;Gain of catalytic residue at M1793 (P = 9e-04);.;.;.;
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
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: rs137854614; hg19: chr3-38592479;