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

gnomAD frequency: 0.00003  dbSNP: rs531460655

Total submissions: 6

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, the in silico prediction for this alteration is inconclusive. 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
All of Us Research Program, National Institutes of Health	RCV000525474	SCV004835845	uncertain significance	Long QT syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1122 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 14/194590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.