Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002273005 | SCV002557544 | likely pathogenic | Syndromic X-linked intellectual disability Claes-Jensen type | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked intellectual disability, Claes-Jensen type (MIM#300534). (I) 0109 - This gene is associated with X-linked recessive disease. However, mildly affected heterozygous females have been reported (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity, where intra- and interfamillial variability has been reported (PMID: 16541399). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a family with severe intellectual disability, short stature and speech impairment (PMID: 16541399). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has segregated within three hemizygous, affected males from a single family (PMID: 16541399). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Analysis of patient lymphoblastoid cells demonstrates reduced gene and protein expression compared to wildtype controls (PMID: 34356104). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Genetics and Molecular Pathology, |
RCV002273005 | SCV004175205 | likely pathogenic | Syndromic X-linked intellectual disability Claes-Jensen type | 2023-07-03 | criteria provided, single submitter | clinical testing | The KDM5C c.2248C>T variant is classified as LIKELY PATHOGENIC (PS3_supporting, PS4_moderate, PM2, PP3) This variant is a single nucleotide change in exon 16/26 of the KDM5C gene, which is predicted to change the amino acid arginine at position 750 in the protein to tryptophan. This variant is not in dbSNP and is absent from population databases (PM2). This variant has been previously reported in at least two unrelated probands with intellectual disability (PMID: 16541399, ClinVar) (PS4_moderate). This variant has segregated within 3 hemizygous, affected males from a single family (PMID: 16541399) (only single family:PP1 not applied). Functional studies have demonstrated that this variant results in abnormal protein function by reducing gene and protein expression compared to wildtype controls (PMID: 34356104) (PS3_supporting). This variant has been reported in ClinVar (Variation ID: 1699148) and HGMD (Accession no.: CM061211) as Likely pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). |
| Labcorp Genetics |
RCV003750884 | SCV004511660 | likely pathogenic | Spastic paraplegia | 2023-12-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 750 of the KDM5C protein (p.Arg750Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked intellectual disability (PMID: 16541399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1699148). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KDM5C protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KDM5C function (PMID: 34356104). 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. |