rs1060501127

Positions:

• chr3-38550951-CTGAG-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.5417_5420del​(p.Thr1806SerfsTer27) variant causes a frameshift 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1806T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 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 37 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38550951-CTGAG-C is Pathogenic according to our data. Variant chr3-38550951-CTGAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.5414_5417del	p.Thr1805SerfsTer27	frameshift_variant	28/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.5417_5420del	p.Thr1806SerfsTer27	frameshift_variant	28/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5417_5420del	p.Thr1806SerfsTer27	frameshift_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5414_5417del	p.Thr1805SerfsTer27	frameshift_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This sequence change creates a premature translational stop signal (p.Thr1806Serfs*27) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 211 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with atrioventricular block (PMID: 22899775). ClinVar contains an entry for this variant (Variation ID: 406415). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs*10) 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. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2019

The c.5417_5420delCTCA variant, located in coding exon 27 of the SCN5A gene, results from a deletion of 4 nucleotides at nucleotide positions 5417 to 5420, causing a translational frameshift with a predicted alternate stop codon (p.T1806Sfs*27). This alteration has been reported in a subject with atrioventricular block and her similarly affected father (Baruteau AE et al. Circulation, 2012 Sep;126:1469-77). Frameshifts are typically deleterious in nature. Although this frameshift occurs at the 3' terminus of SCN5A and is not expected to trigger nonsense-mediated mRNA decay, it alters more than 10% of the protein. Based on the available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1060501127; hg19: chr3-38592442;