ClinVar Genomic variation as it relates to human health

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); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33370388, 31566912, 33368972, 28679403, 8078586, 8723101, 33511985, 29542187, 7913883, 25614871, 17683901, 25691418, 9857065, 23056398, 19088846, 28230213, 29593476, 21739570, 22339077, 22325359, 28181399, 30160829, 30138938, 34672771, 22045636, 36352425, 36923788)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Gain of function is a known mechanism of disease in this gene and are associated with skeletal dysplasias (MIM#146000, #100800, #187600, #187601; PMID: 17320202). Loss of function and dominant negative mechanisms have been proposed to cause autosomal recessive and dominant CATSHL syndrome, respectively (MIM#610474; PMID: 17033969, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with dominant disease, at least one family has been described with autosomal recessive CATSHL syndrome (PMID: 24864036). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants typically associated with achondroplasia have also been reported in individuals with hypochondroplasia (PMID: 25614871). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane domain (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variants c.1138G>A and c.1138G>C, both resulting in the missense change p.(Gly380Arg), are commonly reported pathogenic and account for approximately 90% of achondroplasia cases with variants in this gene (ClinVar, PMID: 25614871). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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.

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.

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.

PM2_Supporting+PS4+PS3+PS1+PP4

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 gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic.

Common pathogenic variant in achondroplasia