ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1655T>C (p.Leu552Ser) (rs199472918)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223726 SCV000234106 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing The L552S variant in the KCNH2 gene has been published multiple times in association with LQTS, and is considered a founder mutation in the Finnish population (Swan H et al., 1999; Piippo K et al., 2000; Splawski et al., 2000; Marjamaa A et al., 2009). Piippo et al. reported two Finnish siblings with severe LQTS phenotypes who were homozygous for the L552S mutation. Of the 35 relatives who were heterozygous for L552S, the phenotype demonstrated a wide spectrum from asymptomatic to recurrent syncopal spells. Functional studies demonstrated that L552S, located in the S5 domain, displayed a marked increase in both activation and deactivation rates of the potassium channel (Piippo K et al., 2000). Collectively, L552S was not observed in over 400 control chromosomes in various reports (Swan H et al., 1999; Piippo K et al., 2000; Splawski et al., 2000), and the NHLBI Exome Sequencing Project reports L552S was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.
Blueprint Genetics RCV000208055 SCV000263974 pathogenic Long QT syndrome 2 2015-11-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000248595 SCV000320018 pathogenic Cardiovascular phenotype 2019-03-13 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses)
Invitae RCV000543570 SCV000627429 pathogenic Long QT syndrome 2019-08-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 552 of the KCNH2 protein (p.Leu552Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs199472918, ExAC 0.08%). This variant has been reported to segregate with Long QT syndrome in a single family with two affected neonatal homozygotes (PMID: 10841244). This variant also been reported in individuals affected with long QT syndrome (PMID: 10841244, 10973849, 22949429, 21244686). ClinVar contains an entry for this variant (Variation ID: 67225). Experimental studies have shown that this missense change disrupts trafficking of the KCNH2 protein and increases the activation and deactivation rates of the channel in vitro (PMID: 25417810, 10841244). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057934 SCV000089454 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10483966;PMID:10841244;PMID:10973849;PMID:11854117;PMID:12477631;PMID:12690509;PMID:15840476;PMID:19160088;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223726 SCV000280118 pathogenic not provided 2014-10-29 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu552Ser (c.1655T>C) Based on the data reviewed below, we consider it very likely disease causing. This variant has been reported in at least 8 individuals with LQTS in the scientific literature. It is considered a founder mutation in the Finnish population. There is very limited segregation data but one study (Piippo et al. 2000) presented in vitro functional data suggesting this variant increases activation and deactivation rates (see below). This is a non-conservative amino acid substitution in which a nonpolar leucine is replaced with an uncharged polar and small serine at a position that is completely conserved across species (as are neighboring amino acids). In terms of in silico prediction programs, Mutation Taster predicts this variant to be disease causing and PolyPhen predicts probably damaging. The variant occurs in exon 7, which is within the S5 domain of the KCNH2 protein. Mutations in the KCNH2 gene have been reported in approximately 25-35% of patients with autosomal dominant long QT syndrome, and are associated with increased risk of cardiac events triggered by exercise and auditory stimulation (especially during sleep). Variants at nearby residues have been reported in HGMD in association with LQTS (Ala558Glu; Leu559His; Ala561Thr) supporting the functional importance of this region of the protein. There is also a nearby missense variant, p.Gly572Ser, which our team considers to be very likely disease causing. Swan et al. 1999: This L552S variant was identified in one family with LQTS, where the authors vaguely refer to it co-segregating with disease (though they do not include specific numbers). Piippo et al. 2000: Studied two sibs showing prolonged QT and their asymptomatic parents for mutations in the KCNH2 gene. This L552S mutation was identified in heterozygous state in both parents and homozygous state in both severely affected siblings. Authors screened 88 unrelated Finnish probands with LQTS total, identifying this variant in 4 additional families. Thus in total, 6 apparently unrelated families with LQTS were identified with this variant (corresponding to a prevalence rate of 7% among Finnish LQTS families). The mutation was in total identified in 40 individuals across these 6 families and absent from 63 unaffected family members. The authors also performed in vitro functional studies where they transiently expressed L552S in COS7 cells—the mutant displayed a marked increase in both activation and deactivation rates as compared to wild type channels. Absent from 100 controls. Splawski et al. 2000: Screened 262 individuals with LQTS of European ancestry for mutations in 5 LQT genes. All mutations absent from >200 control individuals. This L552S variant was identified in one LQT family in this study. No segregation data was presented. Marjamaa et al. 2009: Genotyped 6,334 subjects over the age of 30 from a population cohort for four Finnish founder mutations (including this KCNH2 variant). The authors state that these four mutations account for up to 70% of the known genetic spectrum of long QT syndrome in Finland. Identified this L552S variant in 2 of 6334 individuals from Finland, where the average QT interval was 442+/- 32 (420-465) in mutation carriers. This variant is identified in several other reviews implicating its role as a Finnish founder mutation (Zhang et al. 2010; Hoffman et al. 2011). In total, this variant is absent from more than 6800 controls derived from publicly available control databases and publications in the scientific literature (including ~6,500 individuals of European and African American descent from the NHLBI Exome Sequencing project; > 200 control individuals from Splawski et al. 2000 and 100 control individuals from Piippo et al. 200). The variant is present in 1 of 93 individuals of Finnish descent in the 1000Genomes project for an overall allele frequency of 0.05%. Legacy names include p.L212S and p.L456S. Please note: while there is a variant listed at this residue in ESP, p.R552C, this is on a different transcript.

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