rs397514251

Positions:

• chr3-38555670-TGGGCTTCTG-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000335.5(SCN5A):​c.4516_4524delCAGAAGCCC​(p.Gln1506_Pro1508del) variant causes a conservative 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_000335.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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]

SCN5A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000335.5.
• 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	Protein	UniProt
SCN5A	NM_001099404.2	c.4519_4527delCAGAAGCCC	p.Gln1507_Pro1509del	conservative_inframe_deletion	26/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4516_4524delCAGAAGCCC	p.Gln1506_Pro1508del	conservative_inframe_deletion	26/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4519_4527delCAGAAGCCC	p.Gln1507_Pro1509del	conservative_inframe_deletion	26/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4516_4524delCAGAAGCCC	p.Gln1506_Pro1508del	conservative_inframe_deletion	26/28	1	NM_000335.5	ENSP00000398266.2

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 21, 2022	- -

Long QT syndrome 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Aug 06, 2024	ACMG Criteria: PM2_P, PS3, PM1, PP5, PM4; Variant was found in a heterozygous state -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 08, 2024

The c.4519_4527del variant in the SCN5A gene is located in exon 26 and results in an in-frame deletion of three amino acid residues (p.Gln1507_Pro1509del) (also known as delQKP-1507-1509). This variant has been observed in multiple unrelated individuals with clinical features of long QT syndrome (LQTS) (PMID: 14654377, 18697752, 23098067, 26467377, 7889574, 24667783). This variant has also been observed to co-segregate with disease in families (PMID:26467377, 14654377). Experimental studies have shown that this variant negatively impacts SCN5A channel function (PMID: 14654377, 18697752, 20728579). This variant is absent in the general population database (gnomAD). ClinVar contains an entry for this variant (ID: 201571). Based on the available evidence, the c.4519_4527del (p.Gln1507_Pro1509del) variant in the SCN5A gene has been classified as pathogenic. -

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 -

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;