rs794728912

chr3-38585944-AC-Achr3-38585944-AC-ACC

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.2533del(p.Val845CysfsTer2) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

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 3-38585944-AC-A is Pathogenic according to our data. Variant chr3-38585944-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38585944-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2533del	p.Val845CysfsTer2	frameshift_variant	16/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2533del	p.Val845CysfsTer2	frameshift_variant	16/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2533del	p.Val845CysfsTer2	frameshift_variant	16/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2533del	p.Val845CysfsTer2	frameshift_variant	16/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 25, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val845Cysfs*2) 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). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 201559). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	Reported in patients with Brugada syndrome or a prolonged QTc (PMID: 20129283, 32009526, 34649698); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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: 20129283, 30662450, 31447099, 34649698, 32009526) -

Brugada syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 12, 2017	The p.Val845fs variant in SCN5A has been reported in 1 individual with suspected Brugada syndrome (Kapplinger 2010) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 201559). It was absent from large popula tion studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 845 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Loss of function variants in SCN5A are typically associated with Brugada syndrome although overlapping presentations in cluding other SCN5A related phenotypes (Long QT syndrome) have been described (R emme 2013). In summary, although additional studies are required to fully establ ish its clinical significance, the p.Val845fs variant is likely pathogenic. ACMG /AMP Criteria applied: PVS1, PM2 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 29, 2015	- -

Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 09, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2021

The c.2533delG pathogenic mutation, located in coding exon 15 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 2533, causing a translational frameshift with a predicted alternate stop codon (p.V845Cfs*2). This alteration has been detected in multiple individuals with confirmed or suspected Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs794728912; hg19: chr3-38627435;