ClinVar Miner

Submissions for variant NM_000142.4(FGFR3):c.749C>G (p.Pro250Arg) (rs4647924)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017746 SCV000328408 pathogenic Muenke syndrome 2016-10-20 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, and hearing loss syndrome; Carcinoma of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Bladder cancer, somatic; 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
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.
Genetic Services Laboratory, University of Chicago RCV000193831 SCV000247376 pathogenic Craniosynostosis 2015-04-30 criteria provided, single submitter clinical testing
ITMI RCV000121075 SCV000085243 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000193831 SCV000640386 pathogenic Craniosynostosis 2018-12-03 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.
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

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