Submission Details

COL2A1 was first reported in relation to autosomal dominant COL2A1-related spondyloepiphyseal dysplasia in 1990 (Tiller et al., PMID: 2339128). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, the following disease entities, spondyloepiphyseal dysplasia congenita, spondyloepiphyseal dysplasia with metatarsal shortening (formerly known as Czech dysplasia), and spondyloepiphyseal dysplasia with metaphyseal changes (SEMD Strudwick type, SMD Algerian type, dysspondyloenchondromatosis, and SMD corner fracture type) have been lumped as a single disease entity based on similarities in inheritance pattern, molecular mechanism, and phenotypic variability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately.

At least 11 unique missense variants and 1 inframe deletion that have been reported in 16 individuals across 10 publications are included in this curation (PMIDs: 2339128, 8244341, 16957471, 32071555, 7738948, 16755660, 18553548, 12925722, 17163530, 25735649). Variants in this gene are segregated in 34 additional family members (PMIDs: 18553548, 16755660, 16957471, 8244341). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Notably, the c.2965C>T (p.Arg989Cys) variant (legacy name Arg789Cys) in COL2A1 has been identified repeatedly in patients with spondyloepiphyseal dysplasia congenita. Pathogenicity of this variant is supported by functional evidence and a mouse model (PMIDs: 15522781, 12968670). Another variant, c.823C>T (p.Arg275Cys), has been also reported in multiple probands with COL2A1-related SED with metatarsal shortening (PMIDs: 7738948, 8244341, 8877930, 14730409, 15266623, 15593085, 16155195, 16755660, 17726487, 18553548, 19764028, 21990059, 23448908, 23928235, 32071555) indicating a mutational hot spot in the C-propeptide of COL2A1 specific to SED with metatarsal shortening. This gene-disease relationship is also supported by expression studies, functional assay, and a mouse model (PMIDs: 3033664, 7806485, 15522781, 12968670). In summary, COL2A1 is definitvely associated with autosomal dominant COL2A1-related spondyloepiphyseal dysplasia. 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 Skeletal Disorders Gene Curation Expert Panel on December 6th, 2021 (SOP version 9).