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

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193831	SCV000247376	pathogenic	Craniosynostosis syndrome	2015-04-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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	2020-11-27	criteria provided, single submitter	clinical testing	Reported in multiple individuals with features overlapping other craniosynostosis syndromes, including Pfeiffer syndrome, Crouzon syndrome, and Saethre-Chotzen syndrome (Bellus et al., 1996; Muenke et al., 1997; Mulliken et al., 1999; Kruszka et al., 2016); however, some of the clinical features of individuals with the above syndromes may be rare in patients with this variant (Muenke et al., 1997); Reported in some individuals with radiographic abnormalities of hands and feet but without craniosynostosis, having normal head size or macrocephaly (Muenke et al., 1997; Kruszka et al., 2016a); Published functional studies demonstrate a damaging effect including disruption of endochondral and perichondrial ossification of the cranial base in mice (Laurita et al., 2011; Yasuda et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11746040, 22622662, 24127277, 28551036, 31837199, 14613973, 26740388, 11424131, 12884424, 23325524, 19449410, 21204234, 22016144, 24705944, 15915095, 21233754, 21403567, 22446440, 23851839, 20592905, 24168007, 11197897, 24728327, 12087222, 20707699, 11428324, 8841188, 10541159, 27683237, 27568649, 26028288, 9279764, 9600744, 17103449, 17036334, 31111620, 31130284, 9042914, 20301588, 32238909, 31564432, 31019026, 32369273, 32382396, 9107244, 18000976, 32510873, 33502061)
Invitae	RCV000193831	SCV000640386	pathogenic	Craniosynostosis syndrome	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
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; Cancer 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	2021-04-01	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000017746	SCV001437547	pathogenic	Muenke syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334261	SCV001527055	pathogenic	Achondroplasia	2018-07-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The p.R250R pathogenic variant is the most common pathogenic variant found in MNKS patients with variable expressivity [PMID 9107244, 9279764]
Blueprint Genetics	RCV000436385	SCV001832430	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000017746	SCV001934470	pathogenic	Muenke syndrome	2021-03-05	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
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
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City	RCV000017746	SCV001469215	pathogenic	Muenke syndrome	2020-05-06	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000436385	SCV001808971	pathogenic	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000436385	SCV001952168	pathogenic	not provided		no assertion criteria provided	clinical testing