rs397514251

chr3-38555670-TGGGCTTCTG-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_001099404.2(SCN5A):c.4519_4527del(p.Gln1507_Pro1509del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.94

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001099404.2
• 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
• PP5: Variant 3-38555670-TGGGCTTCTG-T is Pathogenic according to our data. Variant chr3-38555670-TGGGCTTCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 201571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38555670-TGGGCTTCTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4516_4524del	p.Gln1506_Pro1508del	inframe_deletion	26/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.4519_4527del	p.Gln1507_Pro1509del	inframe_deletion	26/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4519_4527del	p.Gln1507_Pro1509del	inframe_deletion	26/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4516_4524del	p.Gln1506_Pro1508del	inframe_deletion	26/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2022	Functional studies reported that this in-frame deletion results in a persistent inward sodium current (Bennett et al., 1995; Keller et al., 2003); Deletion of only the Q1507 residue results in similar functional abnormalities (Keller et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of three amino acids (Glutamine-Lysine-Proline) in a non-repeat region in the linker region between DIII and DIV in the SCN5A gene (Keller et al., 2003); In silico analysis supports a deleterious effect on protein structure/function; Also known as delKPQ, deltaKPQ, delQKP, or p.Lys1505_Glu1507del (Wang et al., 1995; Tester et al., 2005; Liu et al., 2010; Postema et al., 2011); This variant is associated with the following publications: (PMID: 31535183, 21799153, 24815523, 8917568, 8620612, 20728579, 20102920, 15840476, 26022185, 7889574, 20812931, 28734073, 23098067, 10448858, 30677491, 14654377, 26467377, 18697752, 7651517) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 19, 2022	This variant is also known as delQKP1507–1509 or delKPQ. ClinVar contains an entry for this variant (Variation ID: 201571). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 14654377, 18697752, 26022185). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals with clinical features of long QT syndrome (LQTS) (PMID: 18697752, 23098067, 26467377; Invitae). It has also been observed to segregate with disease in related individuals. This variant, c.4519_4527del, results in the deletion of 3 amino acid(s) of the SCN5A protein (p.Gln1507_Pro1509del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PM4 -

Long QT syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2024

The c.4519_4527delCAGAAGCCC pathogenic mutation (also known as p.Q1507_P1509del) is located in coding exon 25 of the SCN5A gene. This alteration results from an in-frame deletion of 9 nucleotides at positions 4519 to 4527. This results in the deletion 3 amino acids (QKP) at codons 1507 to 1509. This alteration (also known as p.K1505_Q1507del and ΔKPQ) has been described in patients with long QT syndrome in addition to mixed phenotypes including cardiac conduction disease, atrioventricular (AV) block and subsequent development of dilated cardiomyopathy (DCM), and it has been observed to segregate with disease in families (Wang Q et al. Cell, 1995 Mar;80:805-11; Shi R et al. Europace. 2008 Nov;10:1329-35; Asadi M et al. Anatol J Cardiol. 2016 Mar;16:170-4). In functional in vitro analyses, this alteration has adversely affected channel function consistent with gain-of-function effects (Keller DI et al. J Mol Cell Cardiol. 2003 Dec;35:1513-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid region is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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: rs397514251; hg19: chr3-38597161;