Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV001727082 | SCV001961795 | pathogenic | not provided | 2021-07-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001727082 | SCV002284475 | likely pathogenic | not provided | 2023-07-17 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 269 of the COMP protein (p.Asp269Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pseudoachondroplasia (PMID: 34709441; Invitae). ClinVar contains an entry for this variant (Variation ID: 1298752). 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.Asp269 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24595329, 28044000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Neuberg Centre For Genomic Medicine, |
RCV003388609 | SCV004100469 | uncertain significance | Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome | criteria provided, single submitter | clinical testing | The missense variant p.D269N in COMP (NM_000095.2) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The mutation has been detected previously in heterozygous state in an individuals with similar clinical features.The p.D269N variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.D269N missense variant is predicted to be damaging by both SIFT and PolyPhen2. The asparagine residue at codon 269 of COMP is only present in a single other mammalian species: Platypus. The nucleotide c.805 in COMP is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |