ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-34375
• Date last evaluated: 2011-11-09
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/2261
• OMIM: https://omim.org/entry/134934
• Gene Reviews: https://www.ncbi.nlm.nih.gov/books/NBK1116/?term=FGFR3%5Bgenesymbol%5D

Location Information

• 4p16.3
• GRCh37/hg19 chr4: 1,795,039-1,810,599
• See linked regions:
• 4p16.3 terminal (Wolf-Hirshhorn syndrome) region

Evidence for Loss Phenotypes

• Loss of function score: 0
• Strength of Evidence: No evidence for dosage pathogenicity

• Loss of function phenotype comments: While gain of function mutations in FGFR3 contribute to several conditions (Muenke, Crouzon, etc.), there are no case reports with deletion/loss of function mutations to determine whether FGFR3 is a haploinsufficient locus.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 0
• Strength of Evidence: No evidence for dosage pathogenicity

Evidence for triplosensitivity phenotype

PubMed ID	Description
21815251	Cyr (2011): Report of a de novo duplication including CRIPAK, SLBP,TACC3, FGFR3, and LETM1. It is not clear if FGFR3 triplosensitivity contributes to the phenotype observed.
20197130	Hannes (2010): Report of a de novo duplication including SLBP,TACC3, FGFR3, LETM1, and WHSCR1 (complicated also by an inversion in the region). It is not clear if FGFR3 triplosensitivity contributes to the phenotype observed.

• Triplosensitivity phenotype comment: More publications of focal duplications are needed to determine triplosensitivity of FGFR3, specifically. The case reports found are listed here only for correlation with similar cases, not as conclusive evidence of triplosensitivity.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.