Submissions for variant NM_000095.3(COMP):c.1754C>T (p.Thr585Met)

dbSNP: rs312262900

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388112	SCV001588972	pathogenic	not provided	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 585 of the COMP protein (p.Thr585Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with COMP-related skeletal dysplasia (PMID: 9463320, 11565064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40995). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COMP protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on COMP function (PMID: 17570134, 23956175). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001388112	SCV001832239	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001388112	SCV005079025	pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Functional studies demonstrate that T585M mouse models exhibit slow growth, mildly shortened limbs, degeneration of articular cartilage, and reduced chondrocyte proliferation with cellular disorganization (PMID: 17588960); 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: 24595329, 23956175, 17570134, 24558358, 21922596, 9463320, 17588960)
GeneReviews	RCV000033887	SCV000057795	not provided	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome		no assertion provided	literature only
GeneReviews	RCV002054553	SCV000086690	not provided	Multiple epiphyseal dysplasia		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004754281	SCV005362397	pathogenic	COMP-related disorder	2024-08-11	no assertion criteria provided	clinical testing	The COMP c.1754C>T variant is predicted to result in the amino acid substitution p.Thr585Met. This variant has been reported in a few individuals with pseudoachondroplasia (PSACH) or multiple epiphyseal dysplasia (MED) (Briggs et al 1998. PubMed ID: 9463320; Czarny-Ratajczak et al. 2001. PubMed ID: 11565064).  Different substitutions affecting the same amino acid residue (p.Thr585Arg and p.Thr585Lys) have also reported in individuals with PSACH and MED (Briggs et al 1998. PubMed ID: 9463320; Briggs. 2014. PubMed ID: 24595329). Functional studies suggest that p.Thr585Met substitution led to a delayed cellular trafficking of COMP protein (Chen et al 2008. PubMed ID: 17570134) and the p.Thr585Met mice are reported to have a phenotype that resembles human pseudoachondroplasia (Piróg-Garcia et al. 2007. PubMed ID: 17588960). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.