ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1640G>A (p.Arg547His) (rs199473432)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000210414 SCV000190245 uncertain significance Long QT syndrome 2 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000438782 SCV000521609 likely pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing The R887H likely pathogenic variant in the KCNH2 gene has been reported in one individual referred for LQTS testing and was absent in greater than 1,500 reference alleles (Tester et al., 2005). In functional studies, R887H was shown to disrupt PKC alpha-dependent phosphorylation and ultimately inhibit surface expression and current density (Donovan et al., 2012). The R887H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC). Missense variants in the same residue (R887C) and in nearby residues (R885C, R885H, R894C, R894L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Although this substitution occurs at a position that is conserved across species, the R887H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, the R887H variant in the KCNH2 gene is likely pathogenic. However, in order to definitively determine its clinical significance, additional data is required.
Invitae RCV000148534 SCV000543460 uncertain significance Long QT syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 887 of the KCNH2 protein (p.Arg887His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473432, ExAC 0.002%). This variant has been reported in individuals referred for long QT genetic testing (PMID: 15840476, 26743238). ClinVar contains an entry for this variant (Variation ID: 67423). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405), but it is unclear how this variant impacts the function of this protein. Experimental studies have shown that this missense change inhibits surface expression and current density (PMID: 22653970). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058148 SCV000089668 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:17161064;PMID:22378279;PMID:22653970). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER_CC_NCGL; University of Washington Medical Center RCV000148534 SCV000190247 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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