rs1064792926

Positions:

• chr3-38581136-GGGGTGGCAATGCA-G

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.3010_3022delTGCATTGCCACCC​(p.Cys1004fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.10

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]

SCN5A (HGNC:):

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 3-38581136-GGGGTGGCAATGCA-G is Pathogenic according to our data. Variant chr3-38581136-GGGGTGGCAATGCA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406419.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.3010_3022delTGCATTGCCACCC	p.Cys1004fs	frameshift_variant	17/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3010_3022delTGCATTGCCACCC	p.Cys1004fs	frameshift_variant	17/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3010_3022delTGCATTGCCACCC	p.Cys1004fs	frameshift_variant	17/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3010_3022delTGCATTGCCACCC	p.Cys1004fs	frameshift_variant	17/28	1	NM_000335.5	ENSP00000398266.2

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/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2016	Although the c.3010_3022del13 likely pathogenic variant in the SCN5A gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Cystine 1004, changing it to a Proline, and creating a premature stop codon at position 137 of the new reading frame, denoted p.Cys1004ProfsX137. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the SCN5A gene have been reported in HGMD in association with Brugada syndrome or other SCN5A-related disorders (Stenson et al., 2014). Furthermore, the c.3010_3022del13 variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.3010_3022del13 in the SCN5A gene is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2016	While this particular variant has not been reported in the literature, loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 13 nucleotides from exon 17 of the SCN5A mRNA (c.3010_3022delTGCATTGCCACCC), causing a frameshift at codon 1004. This creates a premature translational stop signal (p.Cys1004Profs*137) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064792926; hg19: chr3-38622627;