rs863224533

Positions:

• chr3-38551525-AAG-TAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001099404.2(SCN5A):​c.4845_4847delinsGTA​(p.Tyr1615_Phe1616delinsTer) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.31

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 12 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 76 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38551525-AAG-TAC is Pathogenic according to our data. Variant chr3-38551525-AAG-TAC is described in ClinVar as [Pathogenic]. Clinvar id is 216142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.4842_4844delinsGTA	p.Tyr1614_Phe1615delinsTer	stop_gained	28/28	ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.4845_4847delinsGTA	p.Tyr1615_Phe1616delinsTer	stop_gained	28/28	ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4845_4847delinsGTA	p.Tyr1615_Phe1616delinsTer	stop_gained	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4842_4844delinsGTA	p.Tyr1614_Phe1615delinsTer	stop_gained	28/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2015

This sequence change deletes 3 nucleotides and inserts 3 nucleotides in exon 28 of the SCN5A mRNA (c.4845_4847delCTCinsGTA), creating a premature translational stop signal at codon 1615 (p.Tyr1615*). It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating mutations in SCN5A are known to be pathogenic (PMID: 19251209). Furthermore, another truncation variant at this position has been reported in an individual affected with Brugada syndrome (PMID: 20129283). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224533; hg19: chr3-38593016;