Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000702291 | SCV000831139 | likely pathogenic | Spastic paraplegia | 2021-05-03 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the KDM5C mRNA. The next in-frame methionine is located at codon 166. This variant has not been reported in the literature in individuals with KDM5C-related disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different initiator codon variant (c.2T>C) has been reported in individuals affected with X-linked intellectual disability (PMID: 25666439, 22326837). Experimental studies show that this variant results in the production of an unstable, truncated protein that lacks detectable demethylase activity (PMID: 25666439). This suggests that the methionine residue is critical for KDM5C protein function and that other substitutions at this position may also be pathogenic. |