rs28931614
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM1PM2PP3PP5_Very_Strong
The NM_000142.5(FGFR3):c.1138G>A(p.Gly380Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460854Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 726746
GnomAD4 genome
ClinVar
Submissions by phenotype
Achondroplasia Pathogenic:31
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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. -
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. -
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. -
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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
The observed missense c.1138G>A(p.Gly380Arg) variant in FGFR3 gene has been reported previously in in multiple individuals affected with FGFR3-related skeletal disorders (Accogli et al., 2015; Xue et al., 2014; Georgoulis et al., 2011). This variant has been observed to segregate with disease in related individuals (Stoilov et al., 1995). Functional analysis of this variant in heterologous cells indicates increased dimerization at lower receptor concentrations resulting in ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (Placone and Hristova 2012). A mouse model expressing the p.Gly380Arg variant recapitulates the skeletal alterations observed in affected patients including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression (Lee et al., 2017). The p.Gly380Arg variant is present with allele frequency of 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Gly380Arg is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 380 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
This variant was previously reported in patients with achondroplasia, hypochondroplasia and with both achondroplasia and craniosynostosis [PMID: 22045636, 25614871, 21739570, 25691418]. Around 80% of individuals with achondroplasia have parents with average stature and have achondroplasia as the result of a de novo pathogenic variant and in more than 99% of cases of achondroplasia are caused by the identified variant (c.1138 G>A) and another point mutation (c.1138 G>C) resulting p.Gly380Arg substitution of the gene [PMID: 7913883, 20301331]. Functional studies indicate that the identified variant results in increased dimerization of the gene that subsequently increases its cellular activity in the absence of ligands [PMID: 23056398]. -
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This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (II):PP5;PP4;PP3;PM2;PM1;PS3;PS1 -
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A heterozygous missense variant c.1138G>A in exon 9 of FGFR3 gene (chr4:1806119; Depth: 96x) was detected. 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. 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. -
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The FGFR3 c.1138G>A (p.Gly380Arg) variant has been identified in approximately 90% of individuals with achondroplasia, with most cases reported to occur de novo (Legare JM et al., PMID: 20301331; Xue Y et al., PMID: 25614871). This variant has been reported in the ClinVar database as a pathogenic variant by 51 submitters (Variation ID: 16327) and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant resides within the transmembrane domain, of FGFR3 that is defined as a critical functional domain (Bellus GA et al., PMID: 7847369; Legare JM et al., PMID: 20301331), and computational predictors indicate that the variant is damaging, evidence that correlates with impact to FGFR3 function. Functional studies have demonstrated that the p.Gly380Arg variant leads to the key phenotypic features of achondroplasia in transgenic and knock-in mouse models (Lee YC et al., PMID: 28230213; Segev O et al., PMID: 10607835). The same amino acid change (p.Gly380Arg) resulting from a different nucleotide change, c.1138G>C, has been reported and it is also considered pathogenic (Variation ID: 16328; Legare JM et al., PMID: 20301331). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
_x000D_ Criteria applied: PS1, PS3, PS4, PM1, PM2_SUP, PP3, PP4 -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615 /PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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. -
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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). -
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not provided Pathogenic:14
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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. -
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. -
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FGFR3: PS1, PS2, PM2, PS4:Moderate, PP4 -
PP4, PM2, PS1, PS2, PS4 -
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) -
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FGFR3-related disorder Pathogenic:2
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. -
The FGFR3 c.1138G>A variant is predicted to result in the amino acid substitution p.Gly380Arg. The p.Gly380Arg missense change is a recurrent pathogenic variant and is the most common causative variant in FGFR3 for autosomal dominant achondroplasia (Shiang et al. 1994. PubMed ID: 7913883; Bellus et al. 1995. PubMed ID: 7847369; Xue et al. 2014. PubMed ID: 25614871). This variant is interpreted as pathogenic. -
Hypochondroplasia Pathogenic:1Other:1
Common pathogenic variant in achondroplasia -
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Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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. -
Muenke syndrome Pathogenic:1
PS4, PP4, PP3, PM5, PM2 -
Epidermal nevus Pathogenic:1
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Severe achondroplasia-developmental delay-acanthosis nigricans syndrome Pathogenic:1
This sequence variant is a single nucleotide substitution (G>A) at position 1138 of the coding sequence of the FGFR3 gene that results in a glycine to arginine amino acid change at residue 380 of the fibroblast growth factor receptor 3 protein. This is a well-known variant that has also been referred to as c.1144G>A and p.Gly382Arg in the literature. This residue falls in the transmembrane domain (PMID: 24120763) which plays a critical role in the dimerization of the protein. This is a previously reported variant (ClinVar 16327) that has been observed as the most common variant in individuals affected by achondroplasia (PMID: 20301331, 33942288, 32502767, 31994750, 31299979, 31218223, 30692697, 30138938, 29681095, 25691418, 25614871, 21739570, 18266238). This variant is present in 7 of 1460854 alleles (0.0005%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this glycine to arginine amino acid change would be damaging, and the Gly380 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant find significantly affected dimerization of the protein leading to increased FGFR3 activity (PMID: 23056398, 21324899, 20624921). Additionally, a mouse model expressing the variant recapitulated known achondroplasia patient phenotypes (PMID: 28230213). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP3, PS1, PS3, PS4 -
Connective tissue disorder Pathogenic:1
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Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer;C5774286:Lacrimoauriculodentodigital syndrome 2 Pathogenic:1
PS4+PM6_VeryStrong+PS3+PM2_Supporting -
Camptodactyly-tall stature-scoliosis-hearing loss syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at