rs863224532

Positions:

• chr3-38560210-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.4182C>G​(p.Tyr1394Ter) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.81

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38560210-G-C is Pathogenic according to our data. Variant chr3-38560210-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 216141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38560210-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4182C>G	p.Tyr1394Ter	stop_gained	23/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4179C>G	p.Tyr1393Ter	stop_gained	23/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4182C>G	p.Tyr1394Ter	stop_gained	23/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4179C>G	p.Tyr1393Ter	stop_gained	23/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Reported in one individual referred for Brugada syndrome genetic testing in the published literature (Kapplinger et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 30662450, 20129283) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 216141). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1394*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The p.Y1394* pathogenic mutation (also known as c.4182C>G), located in coding exon 22 of the SCN5A gene, results from a C to G substitution at nucleotide position 4182. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation has been detected in an individual with clinically suspected Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.99
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224532; hg19: chr3-38601701;