Submissions for variant NM_000335.5(SCN5A):c.4516_4524del (p.Gln1506_Pro1508del)

dbSNP: rs397514251

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183165	SCV000235581	pathogenic	not provided	2022-06-15	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000183165	SCV000545036	pathogenic	not provided	2022-05-19	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV002336463	SCV002635161	pathogenic	Cardiovascular phenotype	2024-03-06	criteria provided, single submitter	clinical testing	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.
Dept of Medical Biology, Uskudar University	RCV003318368	SCV004022097	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PM4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000183165	SCV005199069	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing
OMIM	RCV000009962	SCV000030183	pathogenic	Long QT syndrome 3	2005-02-01	no assertion criteria provided	literature only