NM_001099404.2:c.4519_4527dupCAGAAGCCC

Variant names:

• chr3-38555670-T-TGGGCTTCTG
• NM_001099404.2:c.4519_4527dupCAGAAGCCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_001099404.2(SCN5A):​c.4519_4527dupCAGAAGCCC​(p.Pro1509_Ile1510insGlnLysPro) variant causes a conservative inframe insertion 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1509P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 62) in uniprot entity SCN5A_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4519_4527dupCAGAAGCCC	p.Pro1509_Ile1510insGlnLysPro	conservative_inframe_insertion	Exon 26 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4516_4524dupCAGAAGCCC	p.Pro1508_Ile1509insGlnLysPro	conservative_inframe_insertion	Exon 26 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4519_4527dupCAGAAGCCC	p.Pro1509_Ile1510insGlnLysPro	conservative_inframe_insertion	Exon 26 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4516_4524dupCAGAAGCCC	p.Pro1508_Ile1509insGlnLysPro	conservative_inframe_insertion	Exon 26 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with acquired long QT syndrome (PMID: 26715165). This variant is not present in population databases (gnomAD no frequency). This variant, c.4519_4527dup, results in the insertion of 3 amino acid(s) of the SCN5A protein (p.Gln1507_Pro1509dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr3-38597161;