chr3-38554372-C-A

Position:

• chr3-38554372-C-A

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.4720G>T​(p.Glu1574Ter) variant causes a stop gained change involving the alteration of a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E1574E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.86

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 165 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38554372-C-A is Pathogenic according to our data. Variant chr3-38554372-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 691966.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_001099404.2	c.4720G>T	p.Glu1574Ter	stop_gained	27/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4717G>T	p.Glu1573Ter	stop_gained	27/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4720G>T	p.Glu1574Ter	stop_gained	27/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4717G>T	p.Glu1573Ter	stop_gained	27/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Oct 07, 2019

The c.4720G>T p.E1574* variant is absent from large population studies (ExAC no frequency). Loss-of-function mutations in SCN5A lead to lower expression levels of SCN5A or production of defective Nav1.5 proteins and cause Brugada syndrome (PMID: 29798782). According to gnomAD LOF pLI value for SCN5A is 0.913. In addition, computation results of MutationTaster, Provean and SIFT show deleterious effect. Based on this evidences, the c.4720G>T variant matches PVS1, PM2, PP3 criterias and evaluated as Pathogenic. -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Aug 24, 2022

Heterozygous variant NM_198056.3:c.4720G>Tin the SCN5A gene was found on NGS data in male proband (22 y.o., Caucasian) with syncope, aborted cardiac arrest and ICD implanted (PMID: 36091819) No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is absent in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.1.0 (Date of access with 20-05-2024). Clinvar contains an entry for this variant (Variation ID: 691966). Two out of three in silico predictors show that this variant is a subject to nonsense-mediated decay (AutoPVS1, masonmd, NMDEscPredictor). Clinvar contains an entry for this variant (Variation ID: 1739478). In accordance with ACMG(2015) criteria and Enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Likely Pathogenic with following criteria selected: PVS1, PM2. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 10, 2020

Variant summary: SCN5A c.4720G>T (p.Glu1574X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Loss-of-function mutations in SCN5A cause Brugada syndrome. The variant was absent in 249326 control chromosomes. To our knowledge, no occurrence of c.4720G>T in individuals affected with Arrhythmia/Brugada syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;D
Vest4		0.98
GERP RS		3.7

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: rs199473620; hg19: chr3-38595863;