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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 20, 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:: RCV000727147.28

Allele description [Variation Report for NM_000142.5(FGFR3):c.1138G>C (p.Gly380Arg)]

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

Other names:

FGFR3, GLY380ARG, 1138G-C

HGVS:

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

Protein change:

G380R; GLY380ARG

Links:

Genetic Testing Registry (GTR): GTR000500504; UniProtKB: P22607#VAR_004155; OMIM: 134934.0002; dbSNP: rs28931614

NCBI 1000 Genomes Browser:

rs28931614

Molecular consequence:

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

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000706143	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Feb 21, 2017)	germline	clinical testing	Citation Link,
SCV000762848	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8723101, 21739570, 22045636, 22339077, 25614871, 25691418, 28492532
SCV001871012	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 20, 2024)	germline	clinical testing	Citation Link,
SCV002023073	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002049731	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Apr 28, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism.

Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P.

Am J Med Genet. 1996 May 3;63(1):148-54.

PubMed [citation]

PMID:: 8723101

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 (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000706143.2

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000762848.5

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

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 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.

#	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 GeneDx, SCV001871012.3

#	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 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)

#	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, SCV002023073.3

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049731.1

#	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>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.

#	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

Last Updated: Nov 30, 2024

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