ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2254C>T (p.Arg752Trp) (rs199472990)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181845 SCV000234148 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing The R752W pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS (Splawski et al., 2000; Ficker et al., 2000; Anderson et al., 2006; Nagaoka et al., 2008). Splawski et al. (2000) initially reported R752W in one individual tested for LQTS and was absent in at least 400 control alleles. Ficker et al. (2000) identified R752W in a 31-year old woman with a history of syncope and sudden death. Twenty-six of 101 genotyped relatives harbored R752W, and of these 17 individuals had prolonged QT intervals and 6 individuals had a history of syncope (Ficker et al., 2000). Furthermore, R752W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R752W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Moreover, functional studies reported R752W results in a protein trafficking defect (Ficker et al., 2000; Anderson et al. 2006; Jou et al., 2013). In addition, a variant at the same residue (R752Q) has been reported in the Human Gene Mutation Database in association with LQTS, further supporting the functional importance of this residue (Stenson et al., 2014).In summary, R752W in the KCNH2 gene is interpreted as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000058099 SCV000731635 pathogenic Congenital long QT syndrome 2017-10-30 criteria provided, single submitter clinical testing The p.Arg752Trp variant in KCNH2 has been reported in the heterozygous state in at least 5 individuals with long QT syndrome (LQTS; Splawski et al. 2000; Ficker et al. 2000; Nagaoka et al. 2008; Stattin et al. 2012, Itoh et al. 2016), and s egregated with disease in 23 individuals in one family (Ficker et al. 2000). In vitro functional studies provide evidence that the p.Arg752Trp variant may impa ct protein function by causing decreased trafficking to the cell membrane due to its retention in the endoplasmic reticulum (Ficker et al. 2000; Anderson et al. 2006). Additionally, animal models in zebrafish have shown that this variant ca uses decreased cardiac repolarization (Jou et al. 2013). This variant has also b een reported by other clinical laboratories in ClinVar (Variation ID# 67379), an d was absent from large population studies. Other variants at this amino acid po sition (p.Arg752Gln, Arg752Pro) have been reported in association with LQTS in t he Human Gene Mutation Database (HGMD, Stenson 2017). In summary, this variant m eets criteria to be classified as pathogenic for LQTS in an autosomal dominant m anner based upon presence in multiple affected individuals, segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PS3_ Moderate; PS4_Supporting; PP1_Strong; PM5; PM2; PP3.
Ambry Genetics RCV000621587 SCV000738207 likely pathogenic Cardiovascular phenotype 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Invitae RCV000631584 SCV000752666 pathogenic Long QT syndrome 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 752 of the KCNH2 protein (p.Arg752Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individual affected with long QT syndrome and has been found to segregate with the disease in a large multigenerational family (PMID: 10973849, 11009462, 18441445). ClinVar contains an entry for this variant (Variation ID: 67379). Experimental studies have shown that this missense is trafficking deficient in vitro and is not able to functionally complement for the loss of KCNH2 in a zebrafish model (PMID: 11009462, 16432067, 23303164). A different missense substitution at this codon (p.Arg752Gln) has been determined to be pathogenic (PMID: 12621127, 25417810). This suggests that the arginine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000631584 SCV000917556 pathogenic Long QT syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2254C>T (p.Arg752Trp) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This was functionally supported by the observation of an increased duration of action potential (APD) and lower amplitude of the rapid component (IKr) of the delayed rectifier potassium channel (hERG) observed in induced pluripotent stem cellderived cardiomyocytes (iPSC-CMs) derived from affected patients (Chai_2018). The variant was absent in 276286 control chromosomes (gnomAD). The variant, c.2254C>T, has been reported in the literature in multiple individuals affected with Long QT Syndrome including at-least two LQTS families which segregated with disease (Chai_2018, Nagaoka_2008). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058099 SCV000089619 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:10973849;PMID:11009462;PMID:11854117;PMID:16432067;PMID:18441445). 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 RCV000181845 SCV000280123 pathogenic not provided 2013-10-31 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.Arg752Trp Based on the case data, strong segregation data, and absence in general population samples, we consider this variant very likely disease causing. This variant has been reported 4 presumably unrelated individuals with long QT syndrome with strong segregation data in one family. Splawski et al (2000) first reported the variant in an individual with LQTS. Ficker et al (2000) also reported the variant in a woman with a history of syncope and sudden death, her extensive family was genotyped and 26 out of 101 individuals were found to harbor the variant. Of these 23 individuals, 17 had a prolonged QT interval and 6 had a history of syncope. Two families with this variant were included in a genotype-phenotype analysis by Moss et al (2002), however given the list of authors, these are likely the same two families reviewed above. Nagaoka et al (2008) also observed this variant in two members of a Japanese family (phenotype for each family member not reported) in their cohort of patients with long QT syndrome. Stattin et al (2012) observed the variant in 1 of 200 unrelated cases referred for long QT genetic testing in their lab in Sweden. Note that the overall yield was 52% so likely a portion of these patients did not in fact have long QT syndrome. Thirty-five patients with this variant were included in a study on individuals from 7 international long QT registries that included probands and family members who carried pathogenic variants (and either did or did not have prolonged QT intervals) (Goldenberg et al 2011). It is unclear how many families this represents and how many of these cases overlap with prior reports such as Splawski et al (2000) and Moss et al (2002), both from the American registry. Functional studies indicate that the mutant protein is not transported to the cell plasma membrane which is where the wild type protein is found (Ficker et al 200, Anderson et al 2006). Other KCNH2 variants associated with long QT have been found to have trafficking defects (ex. p.Phe805Cys, p.Val822Met). PolyPhen2 predicts the variant to be probably damaging. This is a non-conservative amino acid change with a polar Arginine replace with a non-polar Tryptophan. Additional variants in nearby codons (p.Gly749Val, p.Ala753Ser) as well as the same codon (p.Arg752Gln) have been reported in association with long QT. However, p.Arg752Gln was observed in 1 in individual in the NHLBI Exome Sequencing Project (see below). Of note, the reported proband with p.Arg752Gln was homozygous and had severe in utero presentation; in contrast the heterozygotes had no documentable phenotype (Johnson et al 2003). p.Arg752Trp is in the intracellular c-terminal region of the protein. Variants in the transmembrane pore of the channel confer a higher risk of events and a longer QT than variants outside the pore, like this one (Moss et al 2002, Nagaoka et al 2008). In total the variant has not been seen in ~64,400 laboratory controls, published controls and individuals from publicly available population datasets. Splawski et al (2000) did not identify the variant in 200 presumably healthy individuals of unspecified ancestry. GeneDx reports that p.Arg752Trp was absent in 200 Caucasian and African American controls. The variant is not listed in dbSNP or 1000 Genomes. In addition it is not currently listed in the Exome Aggregation Consortium Dataset which includes variant calls on approximately 64,000 individuals of European, African, Asian, and American descent (as of March 1, 2012).

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