Submissions for variant NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg) (rs4647924)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory,University of Chicago	RCV000193831	SCV000247376	pathogenic	Craniosynostosis	2015-04-30	criteria provided, single submitter	clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000017746	SCV000328408	pathogenic	Muenke syndrome	2016-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000436385	SCV000521019	pathogenic	not provided	2018-10-10	criteria provided, single submitter	clinical testing	The P250R variant in the FGFR3 gene has been reported numerous times in association with FGFR3-related disorders, most often Muenke syndrome (Bellus et al., 1996; Mulliken et al., 1999; Roscioli et al., 2013; Kruszka et al., 2016). The clinical diagnosis of Muenke syndrome is confirmed molecularly by the identification of the P250R pathogenic variant (Kruszka et al., 2016). Phenotypic variability, between and within families, has been demonstrated and ranges from no detectable clinical features to complex craniosynostosis (Kruszka et al., 2016). In a large cohort of patients with P250R, hearing loss was present in almost 71%, developmental delay was reported in approximately 66%, intellectual disability, typically mild, was present in approximately 36%, and ADHD was reported in approximately 24% of these patients (Kruszka et al., 2016). Functional studies in mice have shown that P250R distrupts endochondral ossification (Laurita et al., 2011; Yasuda et al., 2012). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P250R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, P250R has been observed as a de novo variant with confirmed parentage in multiple patients with craniosynostosis previously tested at GeneDx. Therefore, we interpret P250R as a pathogenic variant.
Invitae	RCV000193831	SCV000640386	pathogenic	Craniosynostosis	2019-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 250 of the FGFR3 protein (p.Pro250Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (rs4647924, ExAC no frequency). This variant is clearly defined as a causative allele for Muenke syndrome, but has also been identified in individuals with features of Saethre-Chotzen syndrome or other craniosynostosis syndromes (PMID: 26740388, 9042914, 10861678, 10094188, 15915095). ClinVar contains an entry for this variant (Variation ID: 16340). Experimental studies have shown that this missense change enhances ligand-binding in vitro compared to wild-type (PMID: 14613973), consistent with its role in craniosynostosis. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622712	SCV000740868	pathogenic	Inborn genetic diseases	2015-04-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000626772	SCV000747475	pathogenic	Crouzon syndrome; Seizures; Unilateral renal agenesis; Facial asymmetry; Absence seizures; Coronal craniosynostosis; Infantile axial hypotonia	2017-01-01	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000436385	SCV000861668	pathogenic	not provided	2018-06-20	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763120	SCV000893665	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Carcinoma of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Urinary bladder cancer; Hypochondroplasia; Epidermal nevus; Severe achondroplasia with developmental delay and acanthosis nigricans; Malignant tumor of testis; Carcinoma of colon	2018-10-31	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000017746	SCV000996136	pathogenic	Muenke syndrome	2018-04-24	criteria provided, single submitter	clinical testing	This variant is a well-established cause of Muenke syndrome (PMID: 9042914, 26740388, 20301628). Functional characterization demonstrates that this missense change enhances ligand-binding in vitro compared to wild-type and affects endochondral ossification (PMID: 14613973, 22016144). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.001% (2/267,378) and is thus presumed to be rare. It is a non-conservative amino acid substitution and is predicted by multiple in silico tools to be deleterious to protein function. Based on the combined evidence, the c.749C>G (p.Pro250Arg) variant is classified as pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000017746	SCV000999367	pathogenic	Muenke syndrome		criteria provided, single submitter	clinical testing
Mendelics	RCV000987393	SCV001136681	pathogenic	Hypochondroplasia	2019-05-28	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000017746	SCV001160790	likely pathogenic	Muenke syndrome	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS3, PP2, PP3
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000436385	SCV001247231	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000017746	SCV000038024	pathogenic	Muenke syndrome	2009-02-01	no assertion criteria provided	literature only
OMIM	RCV000017747	SCV000038025	pathogenic	Saethre-Chotzen syndrome	2009-02-01	no assertion criteria provided	literature only
ITMI	RCV000121075	SCV000085243	not provided	not specified	2013-09-19	no assertion provided	reference population