ClinVar Miner

Submissions for variant NM_002241.5(KCNJ10):c.52C>T (p.Arg18Trp) (rs138457635)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187805 SCV000241403 uncertain significance not specified 2016-11-18 criteria provided, single submitter clinical testing The R18W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A different amino acid substitution at the same position (R18Q) has been reported in 8 year-old identical twins with autism, intellectual disability and seizures and their mother who was reported to have a multiple tic disorder, motor clumsiness, obsessive-compulsive symptoms and mood swings (Sicca et al., 2011); however, the R18Q variant is present at a frequency of 1.7% in individuals of European ancestry in the NHLBI Exome Sequencing Project, including two individuals who are reportedly homozygous for this variant, suggesting R18Q may be benign. The R18W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R18W 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, but is not conserved in more distantly related species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000464419 SCV000552198 uncertain significance SeSAME syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 18 of the KCNJ10 protein (p.Arg18Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs138457635, ExAC 0.04%). This variant has not been reported in the literature in individuals with KCNJ10-related disease. ClinVar contains an entry for this variant (Variation ID: 205817). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000717963 SCV000848824 uncertain significance History of neurodevelopmental disorder 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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