Submission Details

COL2A1 has been described in association with Platyspondylic dysplasia-Torrance type (PLSD-T), “a rare skeletal dysplasia characterized by platyspondyly, extremely short limbs, and mild brachydactyly” (Désire et al. 2011). Platyspondylic dysplasia-Torrance type is lethal in the neonatal period (PMID: 14729840). This curation includes patients diagnosed with Platypondylic dysplasia-Luton type, which represents the less severe, non-lethal end of the same spectrum of disease. Causative variants of PLSD-T fall within the C-propeptide region of COL2A1 (PMID: 12961049). 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 10 unique variants (missense, nonsense, frameshift etc.) have been reported in patients with PLSD-T. Genetic and experimental evidence, including two mouse models, support this gene-disease relationship. In summary, COL2A1 is definitively associated with autosomal dominant Platyspondylic dysplasia-Torrance 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 Skeletal Disorders Gene Curation Expert Panel on 2/1/21. Gene Clinical Validity Standard Operating Procedures (SOP) - Version 8.

COL2A1 has been described in association with Platyspondylic dysplasia-Torrance type (PLSD-T), “a rare skeletal dysplasia characterized by platyspondyly, extremely short limbs, and mild brachydactyly” (Désire et al. 2011). Platyspondylic dysplasia-Torrance type is lethal in the neonatal period (PMID: 14729840). This curation includes patients diagnosed with Platypondylic dysplasia-Luton type, which represents the less severe, non-lethal end of the same spectrum of disease. Causative variants of PLSD-T fall within the C-propeptide region of COL2A1 (PMID: 12961049). At least 10 unique variants (missense, nonsense, frameshift etc.) have been reported in patients with PLSD-T. Genetic and experimental evidence, including two mouse models, support this gene-disease relationship. Notably, COL2A1 and Achondrogenesis type 2-hypochondrogenesis has been classified as a definitive gene-disease relationship by the ClinGen Skeletal Disorders Expert Panel. Other conditions associated with COL2A1 (Spondyloepiphyseal dysplasia congenita SEDC, Spondyloepiphyseal dysplasia with marked metaphyseal changes SEMD, Kniest dysplasia, Spondyloperipheral dysplasia, SED with metatarsal shortening (Czech dysplasia), Stickler syndrome type I, Dysplasia of the proximal femoral epiphyses) will be assessed separately (PMID: 31633310). In summary, COL2A1 is definitively associated with autosomal dominant Platyspondylic dysplasia-Torrance 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 Skeletal Disorders Gene Curation Expert Panel on 2/1/21. Gene Clinical Validity Standard Operating Procedures (SOP) - Version 8.