Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000254993 | SCV000321518 | likely pathogenic | not provided | 2016-12-19 | criteria provided, single submitter | clinical testing | The H587R missense variant in the COMP gene has been reported previously in association with Pseudoachondroplasia (PSACH) (Deere et al., 1998). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although H587R is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (T585K/R/M, E583K) have been reported in the Human Gene Mutation Database in association with COMP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies have shown that, although the H587R variant yields minimal effects on collagen binding and secondary protein structure, it disrupts fibril formation and organization (Spitznagel et a., 2004; Schmitz et al., 2006; Weirich et al., 2007; Hansen et al., 2011). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV000254993 | SCV003443225 | pathogenic | not provided | 2022-04-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects COMP function (PMID: 17570134, 20936634). 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 COMP protein function. ClinVar contains an entry for this variant (Variation ID: 40996). This missense change has been observed in individuals with pseudoachondroplasia (PMID: 9880218, 12768438; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 587 of the COMP protein (p.His587Arg). |
| Gene |
RCV000033888 | SCV000057796 | not provided | Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome | no assertion provided | literature only |