ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.167G>T (p.Arg56Leu)

dbSNP: rs199472845
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181931 SCV000234234 likely pathogenic not provided 2024-08-05 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the p.(R56L) variant impacts protein trafficking and current density (PMID: 35688148); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22396785, 35688148)
Labcorp Genetics (formerly Invitae), Labcorp RCV000461590 SCV000543465 uncertain significance Long QT syndrome 2023-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 56 of the KCNH2 protein (p.Arg56Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200557). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the p.Arg56 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11854117; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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