Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413218 | SCV000491180 | likely pathogenic | not provided | 2016-03-22 | criteria provided, single submitter | clinical testing | The E698K variant in the KDM5C gene has been reported as a hemizygous pathogenic variant in two brothers with severe intellectual disability, short stature and macrocephaly (Jensen et al., 2005). The E698K variant was not observed in approximately 6500 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 E698K 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 across species. Functional studies suggest the E698K variant is damaging, as the variant was shown to cause abnormal subcellular localization of the mutant protein, reduced H3K4 tri-demethylase activity and impaired transcriptional repressor abilities in U2OS cells (Tahiliani et al., 2007). Therefore, we interpret E698K as a likely pathogenic variant. |
| Ambry Genetics | RCV000624334 | SCV000741371 | likely pathogenic | Inborn genetic diseases | 2019-08-30 | criteria provided, single submitter | clinical testing | The p.E698K variant (also known as c.2092G>A), located in coding exon 15 of the KDM5C gene, results from a G to A substitution at nucleotide position 2092. The glutamic acid at codon 698 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in two brothers with severe intellectual disability (Jensen LR et al. Am. J. Hum. Genet., 2005 Feb;76:227-36). In addition, in one functional study, authors showed that this alteration retains minimal H3K4 tri-demethylase activity (Tahiliani M et al. Nature, 2007 May;447:601-5). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of intellectual disability (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |