Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000193831 | SCV000247376 | pathogenic | Craniosynostosis syndrome | 2015-04-30 | criteria provided, single submitter | clinical testing | |
Genomic Diagnostic Laboratory, |
RCV000017746 | SCV000328408 | pathogenic | Muenke syndrome | 2016-10-20 | criteria provided, single submitter | clinical testing | |
Gene |
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 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, |
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, |
RCV000436385 | SCV000861668 | pathogenic | not provided | 2018-06-20 | criteria provided, single submitter | clinical testing | |
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, |
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, |
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, |
RCV000017746 | SCV001160790 | likely pathogenic | Muenke syndrome | 2019-12-11 | criteria provided, single submitter | research | ACMG evidence PS3, PP2, PP3 |
Ce |
RCV000436385 | SCV001247231 | pathogenic | not provided | 2020-12-01 | criteria provided, single submitter | clinical testing | |
Department of Medical Genetics, |
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] |
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, |
RCV000017746 | SCV001469215 | pathogenic | Muenke syndrome | 2020-05-06 | no assertion criteria provided | clinical testing |