Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000433591 | SCV000521156 | likely pathogenic | not provided | 2016-12-05 | criteria provided, single submitter | clinical testing | The C371Y variant in the COMP gene has been previously reported in patients with a radiologically confirmed diagnosis of multiple epiphyseal dysplasia (MED) (Kim et al., 2011; Jackson et al., 2012). 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. C371Y 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, X-ray crystallography and protein analysis indicates C371 forms a di-sulfide bond with C351 indicating this residue is important in proper protein structure (Tan et al. 2009). Missense variants at the same (C371S/F) have been reported in the Human Gene Mutation Database in association with COMP-related disorders (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. |
| Invitae | RCV000433591 | SCV003443144 | pathogenic | not provided | 2022-05-03 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 371 of the COMP protein (p.Cys371Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of epiphyseal dysplasia and/or pseudoachondroplasia (PMID: 21922596, 21965141). ClinVar contains an entry for this variant (Variation ID: 381656). 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. This variant disrupts the p.Cys371 amino acid residue in COMP. Other variant(s) that disrupt this residue have been observed in individuals with COMP-related conditions (PMID: 9184241, 12483304, 21965141), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |