Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001843053 | SCV001344589 | uncertain significance | Cardiac arrhythmia | 2019-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with alanine at codon 924 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with epilepsy and sudden death (PMID: 26704558) and in an individual affected with sudden cardiac arrest (PMID: 29884292). A different DNA change (c.2771G>C) resulting in the same amino acid change as this variant has been reported in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has not been identified 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 | RCV002436744 | SCV002747182 | uncertain significance | Cardiovascular phenotype | 2022-05-04 | criteria provided, single submitter | clinical testing | The c.2769_2771delGGGinsAGC variant (also known as p.G924A), located in coding exon 12 of the KCNH2 gene, results from an in-frame deletion of GGG and insertion of AGC at nucleotide positions 2769 to 2771. This results in the substitution of the glycine residue for an alanine residue at codon 924, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |