FGFR3 has been repeatedly described in association with autosomal dominant Thanatophoric Dysplasia Type I, which is characterized by lethal micromelic short limb dysplasia, short ribs, curved and short femurs, with cloverleaf skull in some cases (Rousseau et al. 1995; PMID: 7647778). Cysteine substitutions and stop gain variants in this gene are highly specific to TD1, and are highly causative, and for this reason they are scored at a higher level in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence including assays showing increased binding activity of variant FGFR3 receptor protein (PMIDs: 9438390, 8640234, 14751560). In summary, FGFR3 is definitively associated with autosomal dominant Thanatophoric Dysplasia Type I. 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 Gene Curation Expert Panel on 12/6/2021. Gene Clinical Validity Standard Operating Procedures (SOP) – Version 8.
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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