ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1138G>A (p.Gly380Arg)

dbSNP: rs28931614
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Total submissions: 49
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000255750 SCV000232912 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000255750 SCV000322067 pathogenic not provided 2020-02-17 criteria provided, single submitter clinical testing More than 99% of cases of achondroplasia are caused by this variant (98% cases) and another point mutation (c.1138 G>C, 1% cases) resulting in arginine-for-glycine substitutions in amino acid 380 of the gene (Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate an increase in dimerization of FGFR3 that subsequently increases its cellular activity in the absence of ligands (Placone et al., 2012; Webster et al., 1996); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10360392, 10360393, 21739570, 25691418, 23740942, 23949953, 9857065, 28851938, 21324899, 11186940, 25614871, 11556601, 8599935, 27433940, 16841094, 19088846, 26136890, 8078586, 27370225, 29681095, 28679403, 28850094, 28230213, 28253570, 16475234, 28777845, 18266238, 30138938, 29620724, 30692697, 31218223, 31299979, 30712878, 32502767, 31994750, 32360156, 32668031, 33502061, 32712949, 33240318, 22045636, 23056398, 7913883)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255750 SCV000603711 pathogenic not provided 2023-09-08 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 the 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. PMID: 25691418. 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. PMID: 23949953. Georgoulis G et al. Achondroplasia with synostosis of multiple sutures. Am J Med Genet A. 2011; 155A(8):1969-71. PMID: 21739570. Huggins M et al. Achondroplasia-hypochondroplasia complex in a newborn infant. Am J Med Genet. 1999; 84(5):396-400.PMID: 10360392. 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. PMID: 19088846. Lee Y et al. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep. 2017; 7:43220. PMID: 28230213. 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. PMID: 23056398. Rousseau F et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994; 371(6494):252-4. PMID: 8078586. 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. PMID: 25614871.
Invitae RCV000255750 SCV000640354 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 380 of the FGFR3 protein (p.Gly380Arg). This variant is not present in population databases (gnomAD 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.
Baylor Genetics RCV000017724 SCV000854611 pathogenic Achondroplasia 2021-12-27 criteria provided, single submitter clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000017724 SCV000891576 pathogenic Achondroplasia 2017-12-30 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV000763121 SCV000893666 pathogenic Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Malignant tumor of testis; Carcinoma of colon 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000255750 SCV001247233 pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing FGFR3: PS1, PS2, PM2, PS4:Moderate, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center RCV000017724 SCV001251411 pathogenic Achondroplasia 2022-06-24 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS1, PS3, PS4, PM1, PM2_SUP, PP3, PP4
Ambry Genetics RCV001266979 SCV001445160 pathogenic Inborn genetic diseases 2022-03-29 criteria provided, single submitter clinical testing The c.1138G>A (p.G380R) alteration is located in exon 9 (coding exon 8) of the FGFR3 gene. This alteration results from a G to A substitution at nucleotide position 1138, causing the glycine (G) at amino acid position 380 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is the most common alteration to cause achondroplasia and has been reported in many unrelated individuals, including some de novo occurrences (Bellus, 1995; Xue, 2014; Zhang, 2021). Another alteration, c.1138G>C, resulting in the same protein change has been detected in individuals with achondroplasia (Xue, 2014). In HEK293 cells, this variant demonstrated a small, but statistically significant increase in FGFR3 dimerization (Placone, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000255750 SCV001450245 pathogenic not provided 2014-08-15 criteria provided, single submitter clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital RCV000017724 SCV001499907 pathogenic Achondroplasia 2020-12-20 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
Blueprint Genetics RCV000255750 SCV001832499 pathogenic not provided 2020-01-23 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV001731310 SCV001984245 pathogenic not specified 2020-07-28 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000017724 SCV001994790 pathogenic Achondroplasia 2021-05-27 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255750 SCV002023069 pathogenic not provided 2023-12-04 criteria provided, single submitter clinical testing
Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University RCV000017724 SCV002032080 pathogenic Achondroplasia criteria provided, single submitter clinical testing The heterozygous missense variant, c.1138G>A (p.Gly380Arg), in FGFR3 was identified in a patient diagnosed with achondroplasia (ACH). This mutation was commonly identified in ACH patients (Bellus et al., 1995).
Illumina Laboratory Services, Illumina RCV000017724 SCV002038513 pathogenic Achondroplasia 2021-11-11 criteria provided, single submitter clinical testing The FGFR3 c.1138G>A (p.Gly380Arg) variant is a missense variant. Across a selection of literature, the p.Gly380Arg variant has been identified in a heterozygous state in at least 208 individuals (90%) with achondroplasia, occurring in a de novo state in the majority of cases (Bellus et al. 1995; Xue et al. 2014; Legare 2020). Additionally, the p.Gly380Arg variant has been observed in two individuals clinically diagnosed wth hypochondroplasia (Xue et al. 2014). The p.Gly380Arg variant is not reported in the Genome Aggregation Database (version 2.1.1 or version 3.2.1) in a region of good sequence coverage, suggesting that it is a rare variant. Both transgenic and knock-in mouse models that introduced the p.Gly380Arg variant into a human FGFR3 cDNA construct recapitulate the main phenotypic features of achondroplasia in a dose-dependent manner, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development (Segev et al. 2000; Lee et al. 2017). Based on the collective evidence, the p.Gly380Arg variant is classified as pathogenic for achondroplasia.
3billion RCV001807732 SCV002058248 pathogenic Hypochondroplasia 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016327,VCV000016328, PMID:7913883,7913883, PS1_S). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23056398, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.696, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Hypochondroplasia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company RCV000017724 SCV002059334 pathogenic Achondroplasia 2021-08-19 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000017724 SCV002073298 pathogenic Achondroplasia criteria provided, single submitter clinical testing The missense variant p.G380R in FGFR3 (NM_000142.4) is a common mutation implicated in patients with achondroplasia (Pauli M et al). It has been classified as pathogenic in the ClinVar database. There is a moderate physicochemical difference between glycine and arginine. The p.G380R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 380 of FGFR3 is conserved in all mammalian species. The nucleotide c.1138 in FGFR3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
DASA RCV000017724 SCV002097291 pathogenic Achondroplasia 2022-02-14 criteria provided, single submitter clinical testing Same amino acid variant as a previously established pathogenic variant regardless of nucleotide variant (Clinvar ID: 16328; PMID: 20301331) - PS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28230213) - PS3_moderate. The c.1138G>A;p.(Gly380Arg) missense variant has been observed in affected individual(s) (PMID: 32502767; 31994750; 20301331; 31299979; 28230213; 25691418) - PS4. This variant is not present in population databases (rs28931614, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 31994750) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000017724 SCV002507158 pathogenic Achondroplasia 2022-09-05 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV001807732 SCV002507179 pathogenic Hypochondroplasia 2022-05-09 criteria provided, single submitter clinical testing
Mendelics RCV000017724 SCV002516367 pathogenic Achondroplasia 2022-05-04 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276551 SCV002566617 pathogenic Connective tissue disorder 2022-07-19 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000017724 SCV002581623 pathogenic Achondroplasia 2022-07-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000017724 SCV003845153 pathogenic Achondroplasia 2023-02-24 criteria provided, single submitter clinical testing Variant summary: FGFR3 c.1138G>A (p.Gly380Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250348 control chromosomes. c.1138G>A has been reported in the literature in multiple individuals affected with Achondroplasia and observed to segregate with disease (Example: Falik-Zaccai_2000, Stoilov_1995 etc.). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. One study shows that the mutation increases FGFR3 dimerization in a statistically significant way (Placone_2012) and another shows that mice recapitulate the phenotypes observed in ACH patients (dose dependent), including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development (Lee_2017) . Twenty Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=28), VUS (n=1) . Based on the evidence outlined above, the variant was classified as pathogenic.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province RCV000017724 SCV003915585 pathogenic Achondroplasia 2022-01-08 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003227605 SCV003924293 pathogenic Camptodactyly-tall stature-scoliosis-hearing loss syndrome 2023-05-08 criteria provided, single submitter research
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam RCV000017724 SCV003934960 pathogenic Achondroplasia 2022-06-22 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004545731 SCV004046173 pathogenic FGFR3-related disorder criteria provided, single submitter clinical testing This variant has been previously reported as a de novo or heterozygous change in patients primarily with achondroplasia (PMID: 8078586, 22045636, 25614871), while a few individuals have also been described with hypochondroplasia (PMID: 25614871) or with both achondroplasia and craniosynostosis (PMID: 21739570, 25691418).It is absent from the gnomAD population database and thus is presumed to be rare. The c.1144G>A (p.Gly382Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant along with a different nucleotide change at the same location (c.1144G>C, (p.Gly382Arg)) are observed in approximately 90% of individuals with achondroplasia (PMID: 22045636, 25614871). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1144G>A (p.Gly382Arg) variant is classified as Pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000017724 SCV004123078 pathogenic Achondroplasia 2023-07-01 criteria provided, single submitter research
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000017724 SCV004801170 pathogenic Achondroplasia 2024-03-14 criteria provided, single submitter research
New York Genome Center RCV000017724 SCV005044172 pathogenic Achondroplasia 2022-12-07 criteria provided, single submitter clinical testing The de novo heterozygous c.1138G>A p.(Gly380Arg) missense variant is the most common pathogenic variant identified in individuals with achondroplasia [in approximately 98% of cases; PMID:20301331], and has been deposited to ClinVar database by multiple clinical laboratories as Pathogenic [Variation ID: 16327]. The c.1138G>A variant is located in exon 9 of this 18-exon gene and is predicted to replace glycine amino acid with arginine at position 380 of the encoded protein. In silico predictions are in favor of the variant’s deleterious effect [REVEL = 0.696]. In vitro functional studies indicated increased dimerization for the mutant protein resulting in ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (PMID:23056398,19088846). A knock-in mouse model expressing the p.(Gly380Arg) variant recapitulated the phenotypes observed in human achondroplasia patients [PMID:28230213]. Based on the available evidence, the de novo heterozygous c.1138G>A p.(Gly380Arg) missense variant identified in FGFR3 gene is reported here as Pathogenic.
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
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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255750 SCV001740638 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000255750 SCV001967748 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255750 SCV001979494 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000255750 SCV002036538 pathogenic not provided no assertion criteria provided clinical testing
GeneReviews RCV001807732 SCV002318921 not provided Hypochondroplasia no assertion provided literature only Common pathogenic variant in achondroplasia
Department of Genetics, Beijing BioBiggen Technology Co., Ltd. RCV000017724 SCV002546558 pathogenic Achondroplasia 2022-06-29 no assertion criteria provided research
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University RCV000017724 SCV003844101 pathogenic Achondroplasia 2022-03-16 no assertion criteria provided research
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital RCV000017724 SCV005045295 pathogenic Achondroplasia 2024-02-01 no assertion criteria provided clinical testing

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