ClinVar Miner

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

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Total submissions: 16
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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 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

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