Submissions for variant NM_000095.3(COMP):c.1533C>G (p.Asp511Glu)

dbSNP: rs1064794293

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483120	SCV000568694	likely pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing	The D511E variant has been reported previously in association with pseudoachondroplasia (Briggs et al., 2014). The D511E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It 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 at the same (D511Y/H/G) and in nearby residues (D507N/G, p.D509N/V/G/A/E, D515G) have been reported in the Human Gene Mutation Database in association with pseudoachondroplasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000483120	SCV002128415	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp511 amino acid residue in COMP. Other variant(s) that disrupt this residue have been observed in individuals with COMP-related conditions (PMID: 15183431, 17579668, 24595329), which suggests that this may be a clinically significant amino acid residue. 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: 420111). This missense change has been observed in individuals with clinical features of pseudoachondroplasia (PMID: 24595329; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 511 of the COMP protein (p.Asp511Glu).