ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1138G>A (rs28931614)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255750 SCV000232912 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000255750 SCV000322067 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing The G380R variant (c.1138 G>A) in the FGFR3 gene has been reported previously in association with achondroplasia (Shiang et al., 1994), and more than 99% of cases of achondroplasia are caused by this variant and another point mutation (c.1138 G>C) resulting in arginine-for-glycine substitutions in amino acid 380 of the gene (Pauli, 2012). This substitution occurs within the transmembrane domain, and functional studies indicate that G308R results in increased dimerization of FGFR3 that subsequently increases its cellular activity in the absence of ligands (Placone et al., 2012). The G380R missense variant was not observed in large population cohorts (Lek et al., 2016). It 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. We interpret G380R as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999955 SCV000603711 pathogenic none provided 2020-07-02 criteria provided, single submitter clinical testing The FGFR3 c.1138G>A; p.Gly380Arg variant (rs28931614) is the most common alteration identified in individuals with achondroplasia (Accogli 2015, Bessenyei 2013, Georgoulis 2011, Rousseau 1994, Xue 2014). Functional characterization of the variant protein in heterologous cells indicates increased dimerization at lower receptor concentrations (Placone 2012), resulting in ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (Krejci 2008). A mouse model expressing the p.Gly380Arg variant recapitulates the skeletal alterations observed in human achondroplasia patients (Lee 2017). The variant is listed as pathogenic in ClinVar (Variation ID: 16327), and it is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, the p.Gly380Arg variant is considered to be pathogenic. References: Accogli A et al. Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition? Am J Med Genet A. 2015; 167A(3):646-52. Bessenvei B et al. Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association. Am J Med Genet A. 2013; 161A(10):2641-4. Chitayat D et al. Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. Am J Med Genet. 1999; 84(5):401-5. Georgoulis G et al. Achondroplasia with synostosis of multiple sutures. Am J Med Genet A. 2011; 155A(8):1969-71. Huggins M et al. Achondroplasia-hypochondroplasia complex in a newborn infant. Am J Med Genet. 1999; 84(5):396-400. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008; 3(12):e3961. Lee Y et al. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep. 2017; 7:43220. Placone J et al. Direct assessment of the effect of the Gly380Arg achondroplasia mutation on FGFR3 dimerization using quantitative imaging FRET. PLoS One. 2012; 7(10):e46678. Rousseau F et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994; 371(6494):252-4. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014; 2(6):497-503.
Invitae RCV000543572 SCV000640354 pathogenic Craniosynostosis syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 380 of the FGFR3 protein (p.Gly380Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (rs28931614, ExAC no frequency). This is the most commonly observed variant in individuals with achondroplasia, accounting for ~70% of reported cases (PMID: 22045636, 25614871). It has also been reported in a few individuals with hypochondroplasia (PMID: 25614871) or with both achondroplasia and craniosynostosis (PMID: 21739570, 25691418). ClinVar contains an entry for this variant (Variation ID: 16327). A different variant (c.1138G>C) giving rise to the same protein effect observed here (p.Gly380Arg) has also been reported in individuals with achondroplasia. Together, these two variants (c.1138G>A and c.1138G>C) are observed in ~90% of individuals with achondroplasia (PMID: 22045636, 25614871). For these reasons, this variant has been classified as Pathogenic.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000017724 SCV000891576 uncertain significance Achondroplasia 2017-12-30 criteria provided, single submitter curation
Fulgent Genetics,Fulgent Genetics RCV000763121 SCV000893666 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255750 SCV001247233 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000017724 SCV001251411 pathogenic Achondroplasia 2019-10-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266979 SCV001445160 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255750 SCV001450245 pathogenic not provided 2014-08-15 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000255750 SCV001715831 pathogenic not provided 2020-09-08 criteria provided, single submitter clinical testing
OMIM RCV000017724 SCV000038001 pathogenic Achondroplasia 2011-04-15 no assertion criteria provided literature only
OMIM RCV000029207 SCV000051853 pathogenic Epidermal nevus 2011-04-15 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000017724 SCV000109628 pathogenic Achondroplasia 2016-03-08 no assertion criteria provided clinical testing
Baylor Genetics RCV000017724 SCV000854611 pathogenic Achondroplasia 2018-11-18 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000017724 SCV000863902 pathogenic Achondroplasia 2018-06-18 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000017724 SCV001469248 pathogenic Achondroplasia 2020-10-11 no assertion criteria provided clinical testing

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