NM_001099404.2:c.5529_5543delGAGTGGGGACCGCAT

Variant names:

• chr3-38550828-GATGCGGTCCCCACTC-G
• rs794728916
• NM_001099404.2:c.5529_5543delGAGTGGGGACCGCAT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_001099404.2(SCN5A):​c.5529_5543delGAGTGGGGACCGCAT​(p.Ser1844_Ile1848del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Interaction with FGF13 (size 62) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001099404.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5529_5543delGAGTGGGGACCGCAT	p.Ser1844_Ile1848del	disruptive_inframe_deletion	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5526_5540delGAGTGGGGACCGCAT	p.Ser1843_Ile1847del	disruptive_inframe_deletion	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5529_5543delGAGTGGGGACCGCAT	p.Ser1844_Ile1848del	disruptive_inframe_deletion	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5526_5540delGAGTGGGGACCGCAT	p.Ser1843_Ile1847del	disruptive_inframe_deletion	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Feb 14, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201563). This sequence change deletes 15 nucleotides from exon 28 of the SCN5A mRNA (c.5529_5543delGAGTGGGGACCGCAT). This leads to the deletion of 5 amino acid residue(s) in the SCN5A protein (p.Ser1844_Ile1848del) but otherwise preserves the integrity of the reading frame. -

Apr 20, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5529_5543del variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. c.5529_5543del results in an in-frame deletion of five amino acids positions 1844-1848 in the SCN5A gene. Other in-frame deletions have been reported in the SCN5A gene in association with arrhythmia. With the clinical and molecular information available at this time, we cannot definitively determine if c.5529_5543del is a disease-causing mutation or a rare benign variant. -

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: rs794728916; hg19: chr3-38592319;