ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2383G>A (p.Val795Ile)

gnomAD frequency: 0.00002  dbSNP: rs1002588450
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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 RCV001842054 SCV001733694 uncertain significance Cardiac arrhythmia 2021-11-04 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 795 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/250974 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 RCV002458502 SCV002737721 uncertain significance Cardiovascular phenotype 2022-02-23 criteria provided, single submitter clinical testing The p.V795I variant (also known as c.2383G>A), located in coding exon 9 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2383. The valine at codon 795 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a long QT syndrome genetic testing cohort; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). This amino acid position is highly conserved in available 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002568049 SCV002933290 uncertain significance Long QT syndrome 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 795 of the KCNH2 protein (p.Val795Ile). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 1171063). 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 disruptive. 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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