Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000486483 | SCV000571967 | likely pathogenic | not provided | 2016-10-20 | criteria provided, single submitter | clinical testing | A novel I273M variant that is likely pathogenic has been identified in the KCNQ2 gene. The I273M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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. This substitution alters a conserved position predicted to be within the pore forming loop between the S5 and S6 transmembrane segments. Missense variants in nearby residues (L268F, G271V, T274M, T276I, T277I) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I273M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |