ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1490A>G (p.Asp497Gly) (rs199473004)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181873 SCV000234176 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The D837G pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS, and this variant was absent from 1,488 control alleles (Khositseth et al., 2004; Tester et al., 2005; Partemi et al., 2014). In addition, the NHLBI Exome Sequencing Project reports D837G 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. The D837G 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. This substitution also occurs at a position that is conserved across species and islocated in the cyclic-nucleotide-binding homology domain (CNBHD). Moreover, functional studies have shown that variants in the CNBHD can cause incorrect folding that can lead to protein instability and ultimately deficient protein trafficking (Li et al., 2016; Anderson et al., 2014). Furthermore, pathogenic missense variants at the same residue (D837N, D837Y), as well as variants in nearby residues (R835W, R835Q, V841L, P846S, P846T) have been reported in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, D837G in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000469039 SCV000543440 likely pathogenic Long QT syndrome 2016-05-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 837 of the KCNH2 protein (p.Asp837Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple individuals affected with long QT syndrome (PMID: 25119684, 21440677). ClinVar contains an entry for this variant (Variation ID: 67407). One experimental study has shown that this missense change causes a protein trafficking deficiency in vitro (PMID: 25417810). In summary, this is variant is a missense change that is absent in the general population and reported in multiple individuals affected with long QT syndrome. In addition, it has been shown to affect protein function in vitro. For these reasons, it has been classified as Likely Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000677334 SCV000803595 likely pathogenic Long QT syndrome 2 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Long QT syndrome 2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Mutation found in multiple unrelated patients and absent from population databases.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058131 SCV000089651 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:15840476;PMID:15851119). 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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