ClinVar Miner

Submissions for variant NM_002241.5(KCNJ10):c.250G>A (p.Val84Met) (rs140646329)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187807 SCV000241405 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNJ10 gene. The V84M variant was previously identified as a heterozygous change in an individual with complex partial seizures, severe intellectual disability, and autism; however, this variant was also identified in multiple unaffected family members (Sicca et al., 2011). Although functional studies suggest that V84M results in a gain-of function that leads to neuronal hyperexcitability and altered synaptic function (Sicca et al., 2011; Sicca et al., 2016), no other nearby gain of function variants have been reported in the Human Gene Mutation Database in association with KCNJ10-related disorders (Stenson et al., 2014). The V84M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The V84M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000807727 SCV000947796 uncertain significance SeSAME syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 84 of the KCNJ10 protein (p.Val84Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs140646329, ExAC 0.01%). This variant has been observed as heterozygous in an individual affected with focal seizures, autism, and developmental delay. (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205819). Experimental studies have shown that this missense change results in hyper-excitability and surface expression of the KCNJ10 channel (PMID: 21458570, 27677466). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.