The relationship between COL3A1 and Ehlers-Danlos syndrome, vascular type (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of February 25th, 2019. Variants in COL3A1 were first reported in humans with this disease as early as 1988 (Superti-Furga et al., PMID 2834369). At least 600 unique variants are found in the Ehlers Danlos Syndrome Variant Database and ~250 more in ClinVar (Byers, 1999; PMID 20301667). This is a well-known gene-disease relationship and there is a significant amount of case-level, segregation and experimental data in the literature, therefore the maximum points for genetic and experimental evidence has been reached. The mechanism for disease is mainly gain-of-function as most cases result from missense variants leading to the substitution of a crucial glycine in the repetitive Gly-X-Y sequence of the triple helix domain, resulting in only 1 in 8 normal mature collagen homotrimers. About 5% of cases are due to haploinsufficiency and are associated with milder phenotypes (Frank et al., 2015; PMID 25758994). This gene-disease relationship is supported by in vitro assays, expression studies, and animal models. In summary, COL3A1 is definitively associated with autosomal dominant Ehlers Danlos Syndrome, vascular 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 General GCEP on February 27, 2019 (SOP Version 6).
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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