Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001377132 | SCV001574372 | likely pathogenic | not provided | 2021-09-17 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Asp439 amino acid residue in COMP. Other variant(s) that disrupt this residue have been observed in individuals with COMP-related conditions (PMID: 15756302, 24595329, 26377240), which suggests that this may be a clinically significant amino acid residue. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces aspartic acid with glutamic acid at codon 439 of the COMP protein (p.Asp439Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of multiple epiphyseal dysplasia and/or pseudoachondroplasia (PMID: 24595329; Invitae). |
| Foundation for Research in Genetics and Endocrinology, |
RCV003232336 | SCV003929415 | likely pathogenic | Multiple epiphyseal dysplasia type 1 | 2023-06-02 | criteria provided, single submitter | clinical testing | A heterozygous missense substitution (p.Asp439Glu ) lies in exon 13 of the PSACH gene and alters a highly conserved residue in the protein.The variant has not been reported in the 1000 Genomes and gnomAD databases. In silico prediction tools (FATHMM, Mutation Assessor, Mutation Taster and SIFT) predicts the variant to be damaging. In summary, the variant meets our criteria to be classified as likely pathogenic. |
| Gene |
RCV001377132 | SCV005333487 | likely pathogenic | not provided | 2023-10-20 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33748277, 34709441) |