ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.3365C>T (p.Pro1122Leu)

gnomAD frequency: 0.00003  dbSNP: rs531460655
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001704869 SCV000234220 uncertain significance not provided 2023-07-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000525474 SCV000627485 uncertain significance Long QT syndrome 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1122 of the KCNH2 protein (p.Pro1122Leu). This variant is present in population databases (rs531460655, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 200534). 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.
Color Diagnostics, LLC DBA Color Health RCV001842839 SCV001347040 uncertain significance Cardiac arrhythmia 2023-04-24 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1122 of the KCNH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has been identified in 14/194590 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.
Ambry Genetics RCV002453653 SCV002612942 uncertain significance Cardiovascular phenotype 2020-07-31 criteria provided, single submitter clinical testing The p.P1122L variant (also known as c.3365C>T), located in coding exon 15 of the KCNH2 gene, results from a C to T substitution at nucleotide position 3365. The proline at codon 1122 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine 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.
Dept of Medical Biology, Uskudar University RCV000525474 SCV004022041 uncertain significance Long QT syndrome 2024-01-08 criteria provided, single submitter research Criteria: PP2, BP4

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