Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000187806 | SCV000241404 | likely pathogenic | not provided | 2014-04-15 | criteria provided, single submitter | clinical testing | p.Thr74Ile (ACC>ATC): c.221 C>T in exon 2 of the KCNJ10 gene (NM_002241.4). The T74I variant has not been published as a mutation, nor has it been reported as a benign polymorphism 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. The T74I 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. This substitution occurs at a position that is conserved in mammals in the M1 transmembrane domain of the KCNJ10 protein and missense mutations in nearby residues (V84M, G77R, F75L) have been reported in association with epilepsy, supporting the functional importance of this region of the KCNJ10 protein. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. 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 EPILEPSY panel(s). |
Invitae | RCV000646754 | SCV000768539 | uncertain significance | EAST syndrome | 2020-02-22 | 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with KCNJ10-related disease. ClinVar contains an entry for this variant (Variation ID: 205818). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 74 of the KCNJ10 protein (p.Thr74Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. |