Submissions for variant NM_000095.3(COMP):c.1502G>A (p.Gly501Asp)

dbSNP: rs1555791425

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520014	SCV000617663	likely pathogenic	not provided	2017-07-13	criteria provided, single submitter	clinical testing	The G501D variant in the COMP gene has previously been reported in at least 3 individuals with clinically and radiographically confirmed multiple ephiphyseal dysplasia, and was found to be de novo in at least one individual (Jackson et al., 2012). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G501D variant 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. Based on currently available evidence, we interpret G501D as a likely pathogenic variant.
CeGaT Center for Human Genetics Tuebingen	RCV000520014	SCV001246166	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000520014	SCV004297274	pathogenic	not provided	2023-05-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly501 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 449473). This missense change has been observed in individual(s) with epiphyseal dysplasia (PMID: 21922596). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 501 of the COMP protein (p.Gly501Asp).