ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1645T>G (p.Leu549Val) (rs765427343)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181878 SCV000234181 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing The L889V variant of uncertain significance in the KCNH2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified independently and/or in conjunction with additional cardiogenetic variants in several unrelated individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. The L889V variant is observed in 21/273922 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The L889V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000526801 SCV000627465 likely benign Long QT syndrome 2017-11-13 criteria provided, single submitter clinical testing
Color RCV000777934 SCV000914031 uncertain significance Arrhythmia 2018-06-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in an individual affected with cardiovascular disorders in the literature. This variant has been identified in 14/10142 Ashkenazi Jewish chromosomes (0.14%) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181878 SCV000924814 uncertain significance not provided 2017-01-18 no assertion criteria provided provider interpretation Testing for our patient was done at GeneDx. Given the lack of case data and its presence at a relatively high minor allele frequency in one subpopulation, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature, to our knowledge. According to the test report: "The L889V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues sharesimilar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function." The Leucine at codon 889 is conserved across species, as are neighboring amino acids. The variant was reported online in 20 of 124,642 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 13 of 4931 individuals of Ashkenazi Jewish descent (0.13% MAF), 4 of 55,513 individuals of European (non-Finnish) descent (0.0036% MAF) and 3 of 3161 individuals of "other" descent (0.0475% MAF). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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