chr3-38551487-G-A

Position:

chr3-38551487-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000423572.7(SCN5A):c.4882C>T(p.Arg1628Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,956 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1628R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.94

Variant links:

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]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 129 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38551487-G-A is Pathogenic according to our data. Variant chr3-38551487-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551487-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4885C>T	p.Arg1629Ter	stop_gained	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.4882C>T	p.Arg1628Ter	stop_gained	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4885C>T	p.Arg1629Ter	stop_gained	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4882C>T	p.Arg1628Ter	stop_gained	28/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251298

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2024	Identified in patients with known or suspected Brugada syndrome in the published literature (PMID: 30050137, 20129283); Identified in a patient with possible long QT syndrome in the published literature (PMID: 27871843); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the sodium current is abolished (PMID: 30050137, 25829473); Nonsense variant predicted to result in protein truncation, as the last 388 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 30050137, 30662450, 30193851, 30203441, 34649698, 33131149, 20129283, 27871843, 25829473) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 27, 2019	PVS1_Strong, PM1, PS3_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change creates a premature translational stop signal (p.Arg1629) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs199473284, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 25829473). ClinVar contains an entry for this variant (Variation ID: 264276). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 25829473). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs10) have been determined to be pathogenic (PMID: 17897635, 18361072). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Mar 11, 2023

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2018

The p.R1629* pathogenic mutation (also known as c.4885C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4885. This changes the amino acid from an arginine to a stop codon within coding exon 27. In a study of Brugada syndrome clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). In addition, a young adult with Brugada syndrome was described to be compound heterozygous for this mutation in conjunction with another SCN5A alteration on the opposite chromosome, and induced pluripotent stem cell-derived cardiomyocytes generated from this patient exhibited significantly reduced sodium current. The p.R1629* mutation co-segregated with disease from parent to child, and in vitro functional analyses indicated p.R1629* sodium channels have virtually no activity (Tan BY et al. Europace. 2015:1-8.doi:10.1093/europace/euv058; Ma D et al. Sci Rep. 2018;8:11246).Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

Vest4

0.95

GERP RS

3.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over