ClinVar Genomic variation as it relates to human health

This MATN3 variant (rs104893637) is absent from a large population dataset and has an entry in ClinVar. It has been identified in approximately 40 percent of individuals with EDM5. Three bioinformatics tools queried predict that p.Arg121Trp would be damaging. The arginine residue at this position is conserved across most vertebrate species assessed. Analysis of cartilage from a patient with the p.Arg121Trp variant showed retention of matrilin-3 protein within the rough endoplasmic reticulum (rER) of chondrocytes. This variant is not predicted to affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.361C>T to be likely pathogenic.

The MATN3 c.361C>T variant is classified as a PATHOGENIC variant (PS4, PM1, PM2, PP3, PP4) This variant is a single nucleotide change in the MATN3 gene which is predicted to change the amino acid arginine at position 121 in the protein to tryptophan. The variant is in exon 2/8 of the MATN3 gene and is located in protein domain: von Willebrand factor A-like domain (vWF A-domain), of the MATN3 gene. Studies have demonstrated that MED mutations in MATN3 are predominantly located in exon 2, which encodes the vWF A-domain (PMID: 16287128; 15459972) (PM1). The variant has been reported in dbSNP (rs104893637) but is absent from population databases (PM2). This variant has been known as a common disease causing variant in the MATN3 gene, and has been reported many times in individuals affected with MED (PMID: 11479597, 21965141, 14729835, 16287128, 15459972, GeneReview) (PS4). The variant has been reported in ClinVar (Variation ID: 7541) as likely pathogenic (1)/ pathogenic (2). The variant has been reported in HGMD (Accession#: CM012401) as disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). Patient's phenotype is highly specific for a the MATN3 gene (PP4).

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MATN3 function (PMID: 16199550, 18518980). 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 MATN3 protein function. ClinVar contains an entry for this variant (Variation ID: 7541). This missense change has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 11479597, 14729835). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the MATN3 protein (p.Arg121Trp).

European-based studies have identified p.Arg121Trp in 12/33 and p.Thr120Met in 5/33 affected individuals (total = 52%) [Chapman et al 2001; Mostert et al 2003; Jackson et al 2004; Cotterill et al 2005; Fresquet et al 2007; Jackson et al 2012; Author, unpublished data]. In a Japanese population, p.Arg121Trp was identified in 3/9 and p.Thr120Met in 3/9 affected individuals (total = 66%) [Mabuchi et al 2004, Itoh et al 2006]. In a Korean study, p.Arg121Trp was identified in 20/30 and p.Thr120Met was identified in 4/30 affected individuals (total = 80%) [Kim et al 2011].