Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181886 | SCV000234189 | uncertain significance | not provided | 2014-05-14 | criteria provided, single submitter | clinical testing | p.Ala907Thr (GCC>ACC): c.2719 G>A in exon 12 of the KCNH2 gene (NM_000238.2). A variant of unknown significance has been identified in the KCNH2 gene. The A907T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A907T variant was not observed in approximately 3000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these population. The A907T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense mutations in nearby residues (S906L, A913V) have been reported in association with LQTS, supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). |
| Invitae | RCV001219788 | SCV001391744 | uncertain significance | Long QT syndrome | 2019-05-08 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 200486). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 907 of the KCNH2 protein (p.Ala907Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. |