NM_000142.5(FGFR3):c.1138G>A (p.Gly380Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255750.48

Allele description

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

Gene:

FGFR3:fibroblast growth factor receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

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

Other names:

FGFR3, GLY380ARG, 1138G-A

HGVS:

NC_000004.12:g.1804392G>A
NG_012632.1:c.1138G>A
NG_012632.1:g.16081G>A
NM_000142.5:c.1138G>AMANE SELECT
NM_001163213.2:c.1144G>A
NM_001354809.2:c.1138G>A
NM_001354810.2:c.1138G>A
NM_022965.4:c.931-432G>A
NP_000133.1:p.Gly380Arg
NP_000133.1:p.Gly380Arg
NP_001156685.1:p.Gly382Arg
NP_001156685.1:p.Gly382Arg
NP_001341738.1:p.Gly380Arg
NP_001341739.1:p.Gly380Arg
LRG_1021t1:c.1138G>A
LRG_1021t2:c.1144G>A
LRG_1021:g.16081G>A
LRG_1021p1:p.Gly380Arg
LRG_1021p2:p.Gly382Arg
NC_000004.11:g.1806119G>A
NM_000142.4:c.1138G>A
NM_000142.4:c.[1138G>A]
NM_001163213.1:c.1144G>A
NR_148971.2:n.1564G>A
P22607:p.Gly380Arg
c.1138G>A (p.G380R)
c.1138G>A(p.G380R)

Protein change:

G380R; GLY380ARG

Links:

Genetic Testing Registry (GTR): GTR000500505; UniProtKB: P22607#VAR_004155; OMIM: 134934.0001; OMIM: 134934.0027; dbSNP: rs28931614

NCBI 1000 Genomes Browser:

rs28931614

Molecular consequence:

NM_022965.4:c.931-432G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000142.5:c.1138G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001163213.2:c.1144G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354809.2:c.1138G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354810.2:c.1138G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148971.2:n.1564G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000232912	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Aug 22, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25614871, 7913883 Citation Link,
SCV000322067	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 17, 2020)	germline	clinical testing	Citation Link,
SCV000603711	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Sep 8, 2023)	germline	clinical testing	Citation Link,
SCV000640354	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21739570, 25691418, 22045636, 25614871, 28492532
SCV001247233	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2023)	germline	clinical testing	Citation Link,
SCV001450245	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001715831	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001740638	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001832499	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Jan 23, 2020)	germline	clinical testing	Citation Link,
SCV001967748	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001979494	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002023069	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002036538	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	10	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	20	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.

Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ.

Cell. 1994 Jul 29;78(2):335-42.

PubMed [citation]

PMID:: 7913883

Achondroplasia with synostosis of multiple sutures.

Georgoulis G, Alexiou G, Prodromou N.

Am J Med Genet A. 2011 Aug;155A(8):1969-71. doi: 10.1002/ajmg.a.33744. Epub 2011 Jul 7.

PubMed [citation]

PMID:: 21739570

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000232912.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		9	not provided	not provided	not provided

From GeneDx, SCV000322067.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603711.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000640354.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247233.18

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

Description

FGFR3: PS1, PS2, PM2, PS4:Moderate, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		7	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450245.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		13	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740638.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Blueprint Genetics, SCV001832499.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001967748.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001979494.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002023069.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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