3-38633203-GC-GCC

Variant names:

• chr3-38633203-G-GC
• NM_001099404.2:c.104dupG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000335.5(SCN5A):​c.104dupG​(p.Ser36LeufsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.97

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 11 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 3-38633203-G-GC is Pathogenic according to our data. Variant chr3-38633203-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 1803812.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.104dupG	p.Ser36LeufsTer53	frameshift_variant	Exon 2 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.104dupG	p.Ser36LeufsTer53	frameshift_variant	Exon 2 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.104dupG	p.Ser36LeufsTer53	frameshift_variant	Exon 2 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.104dupG	p.Ser36LeufsTer53	frameshift_variant	Exon 2 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Brugada syndrome 1 Pathogenic:1

Oct 10, 2022

Gemeinschaftspraxis fuer Humangenetik Dresden

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.(Ser36Leufs*53) is not listed in HGMD 2022.3, ClinVar, gnomAD (absent from large population studies) and NCBI dbSNP. In the LOVD-Database for SCN5A this variant were submitted by us. This variant is classified as pathogenic based on the protein truncating character. ACMG criteria: PVS1, PM2 -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38674694;