rs199473631

chr3-38551085-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):c.5287G>A(p.Val1763Met) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V1763V) 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:3 O:1
• Conservation: PhyloP100: 7.89

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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 3-38551085-C-T is Pathogenic according to our data. Variant chr3-38551085-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551085-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5287G>A	p.Val1763Met	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5284G>A	p.Val1762Met	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5287G>A	p.Val1763Met	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5284G>A	p.Val1762Met	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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2017	The V1763M pathogenic variant in the SCN5A gene has been reported as a de novo variant in a newborn with congenital LQTS presenting with prenatal bradycardia and postnatal 2:1 atrioventricular block and torsade de pointes ventricular tachycardia (Chang et al., 2004). Similarly, V1763M has been identified as an apparently de novo variant in two unrelated probands with infantile LQTS referred for testing at GeneDx. V1763M was also reported in a 10-year-old child presenting with bradycardia during a viral infection who was subsequently diagnosed with cardiac sinus node dysfunction and found to be compound heterozygous for the V1763M and the D1792N variants in the SCN5A gene (Selly et al., 2012). V1763M has been reported in the published literature in an individual referred for LQTS genetic testing (Tester et al., 2005; Kapplinger et al., 2009), and has also been observed in multiple individuals referred for LQTS testing at GeneDx. The V1763M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).Although the V1763M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs in the S6 transmembrane domain of repeat IV at a position that is conserved across species. Multiple missense variants in nearby residues (I1758V, L1761F, L1761H, M1766V, M1766L, Y1767C, I1768V) and in the same residue (V1763L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, electrophysiological studies demonstrated the V1763M variant causes persistent inwardcurrent due to altered inactivation kinetics (Chang et al., 2004; Ma et al., 2013). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2023	This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 15485686, 23998552, 30847666). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15485686, 23998552). 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. ClinVar contains an entry for this variant (Variation ID: 67974). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1763 of the SCN5A protein (p.Val1763Met). -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PS2, PM2 -

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:15485686;PMID:15840476;PMID:16379539;PMID:19716085). 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	0.80
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	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	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.94
MutPred		0.90		.;.;Loss of catalytic residue at V1763 (P = 0.0261);.;.;Loss of catalytic residue at V1763 (P = 0.0261);.;.;.;
MVP		0.95
MPC		1.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.64
gMVP		0.94

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: rs199473631; hg19: chr3-38592576;