Submissions for variant NM_000095.3(COMP):c.1132G>A (p.Asp378Asn)

dbSNP: rs2145902131

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942221	SCV002236633	pathogenic	not provided	2024-10-12	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 378 of the COMP protein (p.Asp378Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of COMP-related conditions (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1455152). 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%. This variant disrupts the p.Asp378 amino acid residue in COMP. Other variant(s) that disrupt this residue have been observed in individuals with COMP-related conditions (PMID: 15756302, 21922596, 24595329), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004754819	SCV005357287	likely pathogenic	COMP-related disorder	2024-07-02	no assertion criteria provided	clinical testing	The COMP c.1132G>A variant is predicted to result in the amino acid substitution p.Asp378Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant impacts an Aspartic acid residue in a type III repeat motif of the COMP protein, where most pathogenic variants are located (Briggs et al. 2014. PubMed ID: 24595329). Different amino acid changes at the same position (p.Asp378Val and p.Asp378Tyr) have been reported as pathogenic in patients with pseudoachondroplasia and/or multiple epiphyseal dysplasia (Kennedy et al. 2005. PubMed ID: 15756302; Jackson et al. 2012. PubMed ID: 21922596; Briggs et al. 2014. PubMed ID: 24595329), and in one patient, the variant was determined to be de novo (p.Asp378Val, Jackson et al. 2012. PubMed ID: 21922596). This variant is interpreted as likely pathogenic.