ClinVar Miner

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

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Total submissions: 23
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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

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