Submissions for variant NM_000095.3(COMP):c.1569C>A (p.Asn523Lys)

dbSNP: rs137852654

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498353	SCV000589982	likely pathogenic	not provided	2017-07-14	criteria provided, single submitter	clinical testing	The c.1569 C>A nucleotide substitution, resulting in the N523K amino acid change, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.1569 C>G) that also results in the N523K missense substitution has been previously reported in association with multiple epiphyseal dysplasia (Ballo et al., 1997; Jackson et al., 2012). The N523K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N523K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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 in nearby residues (D518N, D518Y, D518H, D518G, T527A, T529A, T529I) have been reported in the Human Gene Mutation Database in association with COMP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret N523K as a likely pathogenic variant.
Invitae	RCV000498353	SCV002171662	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 432270). This missense change has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 9021009, 17133256, 21922596). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 523 of the COMP protein (p.Asn523Lys).