3-38579439-C-T

Position:

• chr3-38579439-C-T

Variant summary

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

The NM_000335.5(SCN5A):​c.3282G>A​(p.Trp1094*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_000335.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.08

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 3-38579439-C-T is Pathogenic according to our data. Variant chr3-38579439-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3285G>A	p.Trp1095*	stop_gained	18/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3282G>A	p.Trp1094*	stop_gained	18/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3285G>A	p.Trp1095*	stop_gained	18/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3282G>A	p.Trp1094*	stop_gained	18/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 406434). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and epilepsy (PMID: 19561025, 23538271). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1095*) 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 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 11, 2021

- -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2018

The p.Trp1095X variant in SCN5A has been reported in 1 individual with Brugada s yndrome (Yamagata 2017), and was absent from large population studies. The same amino acid change resulting from a different variant (c.3284 G>A) has been repor ted in another proband with Brugada syndrome and segregated with disease in 2 af fected relatives (Parisi 2013). The p.Trp1095X variant has also been reported in ClinVar (Variation ID 406434). This nonsense variant leads to a premature termi nation codon at position 1095, which is predicted to lead to a truncated or abse nt protein. Heterozygous loss of function of the SCN5A gene is an established di sease mechanism in Brugada syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp1095X variant i s likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2024

The p.W1095* pathogenic mutation (also known as c.3285G>A), located in coding exon 17 of the SCN5A gene, results from a G to A substitution at nucleotide position 3285. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This variant has been detected in individuals with Brugada syndrome, and segregated with disease in one family with both Brugada syndrome and epilepsy (Catalano O et al. Eur Heart J, 2009 Sep;30:2241-8; Parisi P et al. Epilepsy Res, 2013 Aug;105:415-8; Yamagata K et al. Circulation, 2017 Jun;135:2255-2270). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.48
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.64	D
Vest4		0.88
GERP RS		3.4

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: rs759924541; hg19: chr3-38620930;