ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.157G>C (p.Gly53Arg) (rs199472842)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777695 SCV000913628 likely pathogenic Arrhythmia 2018-05-09 criteria provided, single submitter clinical testing Likely Pathogenic based on current evidence: This variant is a missense variant located in the cytoplasmic N-terminal PAS domain of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown that the mutant protein is defective for protein maturation and trafficking to the cell surface (PMID: 22396785, 25417810, 26958806), but shows normal function if successfully transported to the cell surface (PMID: 26958806). This variant has been reported in multiple long QT syndrome patients (PMID: 10973849, 15635208 15840476) but may also present as concealed long QT syndrome (PMID: 21185501). Another variant at this position (p.Gly53Asp) has also been observed in a long QT syndrome patient (PMID: 19716085). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057924 SCV000089444 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:10187793;PMID:10973849;PMID:15840476;PMID:21536673;PMID:22396785). 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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