ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1681G>A (p.Ala561Thr) (rs199472921)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181805 SCV000234108 pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing The A561T pathogenic variant in the KCNH2 gene has been published previously in multiple individuals with LQTS (Dausse et al., 1996; Splawski et al., 2000; Chugh et al., 2004; Nagaoka et al., 2008; Kapplinger et al., 2009; Brandao et al., 2017). This variant has also been identified de novo (assumed) in an individual referred for genetic testing of LQTS at GeneDx. Chugh et al. (2004) reported two individuals with sudden cardiac death, a 32 year-old female who was heterozygous for the A561T variant and a 37 year old male who was apparently homozygous for A561T. Functional studies have demonstrated that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current and causes defective trafficking of the KCNH2 protein to the plasma membrane (Chugh et al., 2004; Jou et al., 2013). The A561T variant results in a non-conservative amino acid substitution. Located in the pore (S5) domain, this substitution occurs at a position that is conserved across species. Variants in the same residue (A561P, A561V) and in nearby residues (A558E, H562R, H562Q) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Furthermore, the A561T variant is not observed in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000619406 SCV000737602 pathogenic Cardiovascular phenotype 2019-07-19 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification
Ambry Genetics RCV000622380 SCV000742901 pathogenic Inborn genetic diseases 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057939 SCV000089459 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:8877771;PMID:10973849;PMID:11222472;PMID:11854117;PMID:15120823;PMID:15840476;PMID:16379539;PMID:16432067;PMID:18441445;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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