ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.188C>A (p.Pro63His) (rs766379103)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181932 SCV000234235 likely pathogenic not provided 2018-07-25 criteria provided, single submitter clinical testing A P63H variant that is likely pathogenic was identified in the KCNH2 gene. This variant has previously been reported in one individual with suspected LQTS; however, no clinical information or segregation data was provided (Lieve et al., 2013). This variant has also been identified in multiple other unrelated individuals referred for LQTS genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Nevertheless, the P63H variant is not observed in large population cohorts (Lek et al., 2016). P63H 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located in the PAS domain which is thought to participate in the regulation of channel function (Harley et al., 2012). Furthermore, multiple pathogenic or likely pathogenic missense variants in nearby residues (E58K, E58G, E58A, E58D, Q61R, C64Y, C64W, T65P, C66G, F68L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is classified as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000181932 SCV000696022 uncertain significance not provided 2016-04-13 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.188C>A variant is a missense change that alters a conserved nucleotide, resulting in an amino acid change from a non-polar Pro to a positively charged His residue. 4/4 in silico tools predict deleterious outcome (SNPs&GO not captured due to low reliability index). However, at the time of classification, functional studies had not been carried out to confirm these in silico predictions. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0013% (1/79290 chromosomes tested), which does not exceed the maximal expected allele frequency for a pathogenic KCNH2 variant. Additionally, the variant of interest has been reported in at least 1 patient with LQTS from the literature and was classified by a clinical diagnostic center as Pathogenic. Furthermore, multiple nearby missense mutations, such as c.182A>G (p.Q61R), c.185G>A (p.R62Q), c.191G>A (p.C64Y), andc.192C>G (p.C64W), have been reported in association with LQTS, further supporting the functional importance of this region. However, additional clinical information and segregation data are needed to evaluate the clinical significance of this missense change with confidence. Taken together, the variant was classified as a VUS until more information becomes available.
Invitae RCV000631676 SCV000752759 uncertain significance Long QT syndrome 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 63 of the KCNH2 protein (p.Pro63His). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs766379103, ExAC 0.02%). This variant has been reported in an individual referred for long QT testing (PMID: 23631430), and was observed to segregate with disease in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 200559). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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