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

dbSNP: rs28931614

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727147	SCV000706143	pathogenic	not provided	2017-02-21	criteria provided, single submitter	clinical testing
Invitae	RCV000727147	SCV000762848	pathogenic	not provided	2023-12-09	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 missense change has been observed in individuals with achondroplasia (PMID: 8723101, 21739570, 22045636, 22339077, 25614871, 25691418). ClinVar contains an entry for this variant (Variation ID: 16328). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000987394	SCV001136682	pathogenic	Hypochondroplasia	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000727147	SCV001871012	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	More than 99% of cases of achondroplasia are caused by this variant and another point mutation (c.1138 G>A) resulting in arginine-for-glycine substitutions in amino acid 380 of the gene (Foldynova-Trantirkova et al., 2012; Shiang et al., 1994); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33370388, 29593476, 31566912, 33368972, 28679403, 8078586, 8723101, 33511985, 29542187, 7913883, 25614871, 17683901, 25691418, 9857065, 23056398, 19088846, 28230213, 21739570, 22339077, 22325359, 28181399, 30160829, 30138938, 34672771, 22045636)
Revvity Omics, Revvity	RCV000727147	SCV002023073	pathogenic	not provided	2021-04-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727147	SCV002049731	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	The FGFR3 c.1138G>C; p.Gly380Arg variant (rs28931614) is a common pathogenic variant observed in individuals affected with achondroplasia (Rousseau 1994, Xue 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional characterization of the variant protein suggests it causes ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (Krejci 2008). A mouse model expressing the p.Gly380Arg variant recapitulates skeletal alterations observed in human achondroplasia patients (Lee 2017). Additionally, another variant at this codon causing the same amino substitution (c.1138G>A; p.Gly380Arg) is commonly reported in individuals with achondroplasia and is considered pathogenic (Rousseau 1994, Xue 2014). Based on available information, the c.1138G>C; p.Gly380Arg variant is considered to be pathogenic. References: 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 YC et al. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep. 2017 Feb 23;7:43220. PMID: 28230213. Rousseau F et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994 Sep 15;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 Nov;2(6):497-503. PMID: 25614871.
3billion	RCV000017725	SCV002573180	pathogenic	Achondroplasia	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016328). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). A different missense change at the same codon (p.Gly380Lys) has been reported to be associated with FGFR3-related disorder (PMID: 17256796). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000017725	SCV004171370	pathogenic	Achondroplasia		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914850	SCV004735024	pathogenic	FGFR3-related condition	2024-02-02	criteria provided, single submitter	clinical testing	The FGFR3 c.1138G>C variant is predicted to result in the amino acid substitution p.Gly380Arg. The p.Gly380Arg variant has been well documented to be causative for autosomal dominant achondroplasia (see examples: Shiang et al. 1994. PubMed ID: 7913883; Bellus et al. 1995. PubMed ID: 7847369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000017725	SCV000038003	pathogenic	Achondroplasia	1994-09-15	no assertion criteria provided	literature only
GeneReviews	RCV000987394	SCV002318922	not provided	Hypochondroplasia		no assertion provided	literature only	Common pathogenic variant in achondroplasia