COL10A1 was first reported in relation to autosomal dominant metaphyseal chondrodysplasia, Schmid type in 1993 (Warman et al., PMID: 8220429). Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature and bowing of the long bones. Radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora. Twenty variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 20 probands in 7 publications (PMIDs: 8004099, 8220429, 8304336, 20872587, 25542771, 34367232, 36400164) are included in this curation. Most pathogenic variants cluster in the NC1 domain of the COL10A1, critical to the trimerization of COL10A1. COL10A1 is not a fibrillar collagen, so glycine tripeptide substitutions are not a known mechanism of disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by an animal model recapitulating the phenotype observed in human patients, expression studies in fibroblasts, and biochemical function supporting the role of COL10A1 in the calcification and ossification of the growth plate (PMIDs: 30010889, 32913098, 37197316). In summary, there is definitive evidence supporting the relationship between COL10A1 and autosomal dominant metaphyseal chondrodysplasia, Schmid type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date June 24, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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