Submissions for variant NM_000141.5(FGFR2):c.866A>C (p.Gln289Pro)

dbSNP: rs121918497

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000415509	SCV000328375	pathogenic	Pfeiffer syndrome	2016-09-17	criteria provided, single submitter	clinical testing
Invitae	RCV001217538	SCV001389384	pathogenic	FGFR2-related craniosynostosis	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 289 of the FGFR2 protein (p.Gln289Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGFR2-related craniosynostosis syndromes, including Crouzon syndrome, and type 1 Pfeiffer syndrome (PMID: 7655462, 16418739, 19066959). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001572560	SCV001797222	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Within the immunoglobulin-like domain 3, in which pathogenic variants are typically associated with craniosynostosis phenotypes (Kan et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9385368, 23754559, 19066959, 7655462, 11781872, 8644708, 30355600, 7581378, 10712195, 16526917, 22355256, 24656465, 11173845, 12884424, 16470531, 32369273, 16418739, 35591945)
Genetic Services Laboratory, University of Chicago	RCV001572560	SCV002069178	pathogenic	not provided	2018-06-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FGFR2 gene demonstrated a sequence change, c.866A>C, in exon 7 that results in an amino acid change, p.Gln289Pro. This sequence change is absent from population databases (ExAc and GnomAD) and it has been reported in multiple patients with craniosynostosis syndromes including Crouzon syndrome (PMIDs: 7655462, 22355256, 11781872), Pfeiffer syndrome (PMID: 19066959), Jackson-Weiss syndrome (PMID: 7581378) and Saethre-Chotzen Syndrome (PMID: 16526917). The p.Gln289Pro change affects a moderately conserved amino acid residue located in a domain of the FGFR2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln289Pro substitution. The p.Gln289Pro amino acid change occurs in a region of the FGFR2 gene where other missense sequence changes have been described in patients with FGFR2-related disorders. These collective evidences indicate that this sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000415509	SCV004804842	pathogenic	Pfeiffer syndrome	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000014196	SCV000034444	pathogenic	Crouzon syndrome	1996-03-01	no assertion criteria provided	literature only
OMIM	RCV000014197	SCV000034445	pathogenic	Jackson-Weiss syndrome	1996-03-01	no assertion criteria provided	literature only