rs794728914

chr3-38585894-CAA-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.2582_2583del(p.Phe861TrpfsTer90) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F861F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.32

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 3-38585894-CAA-C is Pathogenic according to our data. Variant chr3-38585894-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 201561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38585894-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.2582_2583del	p.Phe861TrpfsTer90	frameshift_variant	16/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.2582_2583del	p.Phe861TrpfsTer90	frameshift_variant	16/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2582_2583del	p.Phe861TrpfsTer90	frameshift_variant	16/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2582_2583del	p.Phe861TrpfsTer90	frameshift_variant	16/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2017	The c.2582_2583delTT pathogenic variant in the SCN5A gene has been previously reported in multiple individuals in association with Brugada syndrome and progressive cardiac conduction disease (Schulze-Bahr et al., 2003; Gaborit et al., 2009; Meregalli et al., 2009; Zumhagen et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Hofman et al., 2013). It has also been shown to segregate with disease in at least one other affected relative in one family (Schulze-Bahr et al., 2003). This variant causes a shift in reading frame starting at codon phenylalanine 861, changing it to a tryptophan, and creating a premature stop codon at position 90 of the new reading frame, denoted p.Phe861TrpfsX90. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.2582_2583delTT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 01, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 201561). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 14961552, 29759671). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe861Trpfs*90) 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). -

Brugada syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Apr 14, 2015

The SCN5A Phe861Trpfs*90 has been previously described in individuals with Brugada syndrome and/or family members undergoing genetic testing (Chockalingam et al, 2012; Kapplinger JD, et al., 2010; Meregalli PG, et al., 2009; Schulze-Bahr E, et al., 2003) and was absent from >1300 controls (Kapplinger JD, et al., 2010). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/) and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the SCN5A Phe861Trpfs*90 variant in a young boy who initially presented with recurrent syncope, and was found to have a type 1 Brugada pattern on ECG. Subsequent family screening revealed 2 other siblings and the mother to be clinically affected, and genetic testing found the variant to co-segregate with disease in this family. The Phe861Trpfs*90 variant is predicted to cause a frameshift at codon 861 and lead to a premature stop codon 90 amino acids downstream. In summary, based on the current literature, rarity in populations, our familial data and that loss-of-function mutations in the SCN5A gene are an established mechanism of disease, we classified the Phe861Trpfs*90 variant as "pathogenic". -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 13, 2023

The c.2582_2583del (p.Phe861Trpfs*90) variant in the SCN5A gene is located on the exon 16 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Phe861Trpfs*90), resulting in an absent or disrupted protein product. The variant has been reported in more than 10 unrelated individuals with Brugada syndrome (PMID: 19808440, 20129283, 31478073). Loss-of-function variants of SCN5A are known to be pathogenic (PMID: 30193851, 29574140). The variant is reported in ClinVar (ID: 201561). The variant is absent in the general population database (gnomAD). Therefore, the c.2582_2583del (p.Phe861Trpfs*90) variant of SCN5A has been classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.2582_2583delTT pathogenic mutation, located in coding exon 15 of the SCN5A gene, results from a deletion of two nucleotides at nucleotide positions 2582 to 2583, causing a translational frameshift with a predicted alternate stop codon (p.F861Wfs*90). This alteration has been reported in multiple Brugada syndrome cohorts (Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8; Gaborit N et al. Eur Heart J, 2009 Feb;30:487-96; Kapplinger JD et al. Heart Rhythm, 2010; Jan;7:33-46; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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

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: rs794728914; hg19: chr3-38627385;