Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181906 | SCV000234209 | likely pathogenic | not provided | 2014-07-16 | criteria provided, single submitter | clinical testing | p.Asp1003Tyr (GAC>TAC): c.3007 G>T in exon 13 of the KCNH2 gene (NM_000238.2). The D1003Y variant that is likely pathogenic was identified in the KCNH2 gene. The D1003Y variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The D1003Y variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The D1003Y residue is class conserved across species. In silico analysis predicts D1003Y is damaging to the protein structure/function. Mutations in nearby residues (N996I, R1005Q, R1007H) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the D1003Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in LQT panel(s). |
| Color Diagnostics, |
RCV003591701 | SCV004357541 | uncertain significance | Cardiac arrhythmia | 2023-07-31 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with tyrosine at codon 1003 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 KCNH2-related disorders in the literature. This variant has been identified in 1/186764 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. |