ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.138C>G (p.Asp46Glu)

gnomAD frequency: 0.00001  dbSNP: rs752503743
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001843092 SCV001346493 uncertain significance Cardiac arrhythmia 2023-11-29 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glutamic acid at codon 46 of the KCNH2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is found within a highly conserved N-terminus region (a.a. 1-130). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with epilepsy (PMID: 31696929). This variant has been identified in 6/244546 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001876025 SCV002162449 uncertain significance Long QT syndrome 2023-07-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 46 of the KCNH2 protein (p.Asp46Glu). This variant is present in population databases (rs752503743, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 921751). 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. 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.
Ambry Genetics RCV002393410 SCV002698360 uncertain significance Cardiovascular phenotype 2019-01-16 criteria provided, single submitter clinical testing The p.D46E variant (also known as c.138C>G), located in coding exon 2 of the KCNH2 gene, results from a C to G substitution at nucleotide position 138. The aspartic acid at codon 46 is replaced by glutamic acid, an amino acid with highly similar properties. Another alteration affecting the same amino acid, p.D46Y (c.136G>T), has been reported in association with long QT syndrome (LQTS) (Szperl M et al. J. Appl. Genet., 2018 Nov;59:463-469). This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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