3-38586012-C-T

Variant names:

• chr3-38586012-C-T
• rs1553700699
• NM_001099404.2:c.2466G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000335.5(SCN5A):​c.2466G>A​(p.Trp822*) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 12 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 3-38586012-C-T is Pathogenic according to our data. Variant chr3-38586012-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 505895.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38586012-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2466G>A	p.Trp822*	stop_gained	Exon 16 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2466G>A	p.Trp822*	stop_gained	Exon 16 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2466G>A	p.Trp822*	stop_gained	Exon 16 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2466G>A	p.Trp822*	stop_gained	Exon 16 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Pathogenic:1

Dec 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp822X variant in SCN5A has been reported in a pair of male monozygotic t wins who died from sudden infant death syndrome (SIDS; Turillazzi 2008). This va riant was absent from large population studies. This same amino acid change (p.T rp822X) from a different cDNA change (c.2465G>A) has also been identified in one individual with Brugada syndrome and segregated with disease in one affected re lative (Keller 2005). In vitro functional studies provide some evidence that the p.Trp822X variant may impact protein function (Keller 2005, Turillazzi 2008). T his nonsense variant leads to a premature termination codon at position 822, whi ch is predicted to lead to a truncated or absent protein. Loss of function varia nts in SCN5A are typically associated with Brugada syndrome although overlapping presentations including other SCN5A related phenotypes (Long QT syndrome) have been described (Remme 2013). In summary, this variant meets criteria to be class ified as pathogenic for Brugada syndrome in an autosomal dominant manner based u pon impact to the protein, functional evidence, and absence from controls. ACMG/ AMP Criteria applied: PVS1, PM2, PP3_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.97
GERP RS		4.4

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: rs1553700699; hg19: chr3-38627503;