VCV000016327.118 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(54)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000142.4(FGFR3):c.[1130T>G;1138G>A]

Identifiers

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

Variation ID: 16327 Accession: VCV000016327.118

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 1804392 (GRCh38) [ NCBI UCSC ] 4: 1806119 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 9, 2016	Nov 24, 2024	Aug 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000142.5:c.1138G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000133.1:p.Gly380Arg	missense
NM_000142.4:c.[1138G>A]
NM_001163213.2:c.1144G>A	NP_001156685.1:p.Gly382Arg	missense
NM_001354809.2:c.1138G>A	NP_001341738.1:p.Gly380Arg	missense
NM_001354810.2:c.1138G>A	NP_001341739.1:p.Gly380Arg	missense
NM_022965.4:c.931-432G>A		intron variant
NR_148971.2:n.1564G>A		non-coding transcript variant
NC_000004.12:g.1804392G>A
NC_000004.11:g.1806119G>A
NG_012632.1:c.1138G>A
NG_012632.1:g.16081G>A
LRG_1021:g.16081G>A
LRG_1021t1:c.1138G>A	LRG_1021p1:p.Gly380Arg
LRG_1021t2:c.1144G>A	LRG_1021p2:p.Gly382Arg
	P22607:p.Gly380Arg

... more HGVS ... less HGVS

Protein change

G380R, G382R

Other names

FGFR3, GLY380ARG, 1138G-A

Canonical SPDI

NC_000004.12:1804391:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA129944 Genetic Testing Registry (GTR): GTR000028677 Genetic Testing Registry (GTR): GTR000323266 Genetic Testing Registry (GTR): GTR000325183 Genetic Testing Registry (GTR): GTR000500504 Genetic Testing Registry (GTR): GTR000500505 UniProtKB: P22607#VAR_004155 OMIM: 134934.0001 OMIM: 134934.0027 dbSNP: rs28931614 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FGFR3		No evidence available	No evidence available	GRCh38 GRCh37	984	1134

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Achondroplasia	Pathogenic/Likely pathogenic (28)	criteria provided, multiple submitters, no conflicts	Aug 26, 2024	RCV000017724.74
Epidermal nevus	Pathogenic (1)	no assertion criteria provided	Apr 15, 2011	RCV000029207.14
not provided	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000255750.57
Achondroplasia Camptodactyly-tall stature-scoliosis-hearing loss syndrome Carcinoma of colon Cervical cancer Crouzon syndrome-acanthosis nigricans syndrome Epidermal nevus Hypochondroplasia Levy-Hollister syndrome Malignant tumor of testis Malignant tumor of urinary bladder Muenke syndrome Severe achondroplasia-developmental delay-acanthosis nigricans syndrome Thanatophoric dysplasia type 1 Thanatophoric dysplasia, type 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763121.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2022	RCV001266979.12
not specified	Pathogenic (1)	criteria provided, single submitter	Jul 28, 2020	RCV001731310.12
Hypochondroplasia	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 9, 2022	RCV001807732.13
Connective tissue disorder	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2022	RCV002276551.10
Camptodactyly-tall stature-scoliosis-hearing loss syndrome	Pathogenic (1)	criteria provided, single submitter	May 8, 2023	RCV003227605.9
Severe achondroplasia-developmental delay-acanthosis nigricans syndrome	Pathogenic (1)	criteria provided, single submitter	May 1, 2024	RCV004783725.1
FGFR3-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV004545731.2
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Malignant tumor of urinary bladder Colorectal cancer Hypochondroplasia LADD syndrome 1 Epidermal nevus Thanatophoric dysplasia type 1 Thanatophoric dysplasia, type 2 Germ cell tumor of testis Muenke syndrome Cervical cancer Camptodactyly-tall stature-scoliosis-hearing loss syndrome Crouzon syndrome-acanthosis nigricans syndrome Severe achondroplasia-developmental delay-acanthosis nigricans syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893666.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV002059334.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	DASA Accession: SCV002097291.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (6) PubMed: 20301331‚ 28230213‚ 32502767‚ 31994750‚ 31299979‚ 25691418 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (May 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypochondroplasia Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002507179.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Number of individuals with the variant: 3 Sex: male
Pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002507158.2 First in ClinVar: May 16, 2022 Last updated: Sep 10, 2022	Publications: DOI: 10.1002/mgg3.96 DOI: 10.1002/mgg3.96 Sex: male
Pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581623.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS1, PS2, PS4, PS3_MOD, PM1, PM2_SUP, PP3	Number of individuals with the variant: 6 Sex: female
Pathogenic (Dec 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000854611.2 First in ClinVar: Feb 19, 2018 Last updated: Mar 11, 2023
Pathogenic (Dec 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Achondroplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891576.2 First in ClinVar: Dec 24, 2018 Last updated: Jun 03, 2023	Geographic origin: Middle East
Pathogenic (Jun 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam Accession: SCV003934960.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Number of individuals with the variant: 2 Geographic origin: Vietnam
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Achondroplasia Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004123078.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640354.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 22045636‚ 25614871‚ 21739570‚ 25691418 Comment: 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). … (more) 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. (less)
Pathogenic (Sep 08, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603711.6 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. (less)
Likely pathogenic (Jun 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073298.4 First in ClinVar: Feb 05, 2022 Last updated: Nov 24, 2024	Comment: 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; … (more) 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. (less) Clinical Features: Abnormality of the skeletal system (present)
Pathogenic (Aug 22, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232912.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 25614871‚ 7913883 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3 Number of individuals with the variant: 9 Sex: mixed
Pathogenic (Aug 15, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450245.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 13
Pathogenic (Dec 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001499907.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (4) PubMed: 32502767‚ 31994750‚ 31299979‚ 28777845 Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: East Asia Geographic origin: China
Pathogenic (Sep 08, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715831.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: Bookshelf: NBK1152 Bookshelf: NBK1152 Number of individuals with the variant: 1
Pathogenic (Jan 23, 2020)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832499.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Skeletal Dysplasias Core Panel
Pathogenic (Jul 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984245.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 Comment: The p.Gly380Arg variant in FGFR3 is the most common pathogenic variant causing Achondroplasia. Two nucleotide changes at the same position (c.1138G>A identified in this patient … (more) The p.Gly380Arg variant in FGFR3 is the most common pathogenic variant causing Achondroplasia. Two nucleotide changes at the same position (c.1138G>A identified in this patient and c.1138G>C) leading to the same amino acid change (p.Gly380Arg) in FGFR3 have been shown to account for >99% individuals with Achondroplasia (PMID: 20301331). In summary this variant meets our criteria to be classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University Accession: SCV002032080.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Publications: PubMed (1) PubMed: 7847369 Comment: 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 … (more) 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). (less) Sex: female Ethnicity/Population group: Thai Geographic origin: Thailand
Pathogenic (Nov 11, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002038513.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021	Publications: PubMed (5) PubMed: 10607835‚ 20301331‚ 25614871‚ 28230213‚ 7847369 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypochondroplasia Affected status: yes Allele origin: germline	3billion Accession: SCV002058248.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:7913883 PMID:7913883 PMID:23056398 PMID:23056398 PMID:25614871 PMID:25614871 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016327,VCV000016328, PMID:7913883,7913883, PS1_S). The … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016327,VCV000016328, PMID:7913883,7913883, PS1_S). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23056398, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.696, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Hypochondroplasia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Anterior scalloping of vertebral bodies (present) , Disproportionate short stature (present) , Frontal bossing (present) , Macrocephaly (present) , Midface retrusion (present) , Narrow chest … (more) Anterior scalloping of vertebral bodies (present) , Disproportionate short stature (present) , Frontal bossing (present) , Macrocephaly (present) , Midface retrusion (present) , Narrow chest (present) , Narrow pelvis bone (present) , Progressive intervertebral space narrowing (present) , Rhizomelia (present) , Short finger (present) , Short nose (present) , Trident hand (present) , Anteverted nares (present) , Wide anterior fontanel (present) (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516367.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Pathogenic (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001251411.2 First in ClinVar: May 31, 2020 Last updated: Jul 23, 2022	Comment: _x000D_ Criteria applied: PS1, PS3, PS4, PM1, PM2_SUP, PP3, PP4
Pathogenic (Jul 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566617.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Feb 17, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322067.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (May 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001994790.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 26, 2023	Method: Exome sequencing
Pathogenic (Feb 24, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003845153.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (4) PubMed: 10979354‚ 28230213‚ 23056398‚ 7702086 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province Accession: SCV003915585.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (5) PubMed: 31299979‚ 31218223‚ 30692697‚ 30138938‚ 29681095
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Camptodactyly-tall stature-scoliosis-hearing loss syndrome Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV003924293.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FGFR3-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046173.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023069.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Achondroplasia Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801170.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 29, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001445160.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 7670477‚ 7847369‚ 23056398‚ 25614871‚ 33942288 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 07, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	New York Genome Center Study: PrenatalSEQ Accession: SCV005044172.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Publications: PubMed (2) PubMed: 20301331‚ 28230213 Comment: 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], … (more) 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. (less) Clinical Features: Short long bone (present) Age: 30-39 weeks gestation Secondary finding: no
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197927.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Sep 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088842.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: 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 … (more) 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]. (less)
Pathogenic (Aug 26, 2024)	criteria provided, single submitter (Hauer et al. (Genet Med. 2018)) Method: clinical testing	Achondroplasia (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV005199950.1 First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024	Comment: This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (II):PP5;PP4;PP3;PM2;PM1;PS3;PS1 Number of individuals with the variant: 1
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247233.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: FGFR3: PS1, PS2, PM2, PS4:Moderate, PS3:Supporting Number of individuals with the variant: 7
Pathogenic (May 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome (Autosomal unknown) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397741.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (18) PubMed: 31994750‚ 25614871‚ 30692697‚ 20624921‚ 31218223‚ 21739570‚ 21324899‚ 25691418‚ 20301331‚ 32502767‚ 31299979‚ 29681095‚ 18266238‚ 24120763‚ 28230213‚ 33942288‚ 23056398‚ 30138938 Comment: 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 … (more) 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 (less)
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399900.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 17033969‚ 17320202‚ 24864036‚ 25614871 Comment: 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 … (more) 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 (less)
Pathogenic (Apr 15, 2011)	no assertion criteria provided Method: literature only	ACHONDROPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038001.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2017	Publications: PubMed (13) PubMed: 7913883‚ 8078586‚ 7649548‚ 8673103‚ 11030304‚ 15517832‚ 11186939‚ 11186940‚ 16766665‚ 16841094‚ 18266238‚ 20624921‚ 21324899 Wilkie, A. O. M., Bochukova, E. G., (more...) Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006. Szabo, J., Bellus, G. A., Kaitila, (more...) Szabo, J., Bellus, G. A., Kaitila, I., Francomano, C. A. Fibroblast growth factor receptor 3 (FGFR3) mutations in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A287-only, 1996. Comment on evidence: In achondroplasia (100800), codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC … (more) In achondroplasia (100800), codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC (tyr). Rousseau et al. (1994) found the gly380-to-arg mutation in all 23 cases of achondroplasia studied (17 sporadic and 6 familial). Twenty-two of the 23 probands had the G-to-A transition; only 1 had the G-to-C transversion (134934.0002). See also Ikegawa et al. (1995). Nucleotide 1138 of the FGFR3 gene may be one of the most mutable bases in the human genome. Wilkie (1997) commented that it seems unlikely to be coincidental that the 3 highest germline point mutation rates described in the human (elevated approximately 1000-fold over background) all concern FGFRs: G380R and P250R in FGFR3 (134934.0014) and S252W in FGFR2 (176943.0010). These 3 mutations result in achondroplasia, Muenke nonsyndromic coronal craniosynostosis, and Apert syndrome (101200), respectively. Increased paternal age associated with achondroplasia and Apert syndrome has long been known, and an exclusively paternal origin of mutation was shown in studies of 57 Apert syndrome patients by Moloney et al. (1996) and in 10 achondroplasia patients by Szabo et al. (1996). In a 24-year-old woman whose fetus was suspected by ultrasonography to have a short-limb disorder, Saito et al. (2000) made the diagnosis of achondroplasia by identifying the 1138G-A mutation using PCR with specific primers. Restriction fragment length polymorphism analysis of PCR products was done with SfcI. DNA for the studies was extracted from maternal plasma; the mutation was not found in maternal leukocytes. Van Esch and Fryns (2004) described acanthosis nigricans in a 9-year-old boy with achondroplasia due to the classic gly380-to-arg mutation in FGFR3. Affected sibs with classic achondroplasia but unaffected parents were described by Henderson et al. (2000) and Sobetzko et al. (2000). Both were apparent instances of germinal mosaicism. In a sperm study of 97 men aged 22 to 80 years, Wyrobek et al. (2006) found associations between increased age and genomic defects as measured by the DNA fragmentation index and increased age and the FGFR3 1138G-A mutation without evidence for an age threshold. However, there was no association between age and frequency of sperm with immature chromatin, aneuploidies/diploidies, FGFR2 mutations causing Apert syndrome, or sex ratio. Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified mosaicism for a double mutation in exon 10 of the FGFR3 gene in 1 patient: the G372C mutation (G370C; 134934.0033) and the G382R mutation. Codons were numbered according to the FGFR3 IIIb isoform. In 3 sibs who were the product of the first and third pregnancies of healthy nonconsanguineous parents, Natacci et al. (2008) identified heterozygosity for the G380R mutation in the FGFR3 gene. The mutation was not found in lymphocytic DNA from the parents; however, DNA analysis of a sperm sample from the 37-year-old father showed the G380R mutation. The authors stated that this was the second reported case of germinal mosaicism causing recurrent achondroplasia in a subsequent conception. He et al. (2010) found that the G380R mutation within the transmembrane domain of FGFR3 increased the phosphorylation of tyr647 and tyr648 within the FGFR3 catalytic domain in the absence of FGF1 and at low FGF1 concentration. They determined that the increased kinase activity of mutant FGFR3 was due to a conformational change. The amino acids that mediate helix-helix contacts in the wildtype dimer are leu377, val381, phe384, and ile387, whereas the mutant dimer interface is rotated to involve ile376, arg380, phe383, ile387, val390, and thr394. The 2 alanines at position 391 face each other directly in the wildtype structure, but are rotated away from each other in the mutant structure. He et al. (2010) hypothesized that the rotation at the dimerization interface would induce a concomitant rotation of the catalytic domains with respect to each other and change their kinetics of kinase activity. He et al. (2011) showed that the G380R mutation decreased the probability of heterodimer formation between mutant and wildtype subunits at low ligand concentration, but not at high ligand concentration. (less)
Pathogenic (Apr 15, 2011)	no assertion criteria provided Method: literature only	NEVUS, EPIDERMAL, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000051853.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2017	Publications: PubMed (13) PubMed: 7913883‚ 8078586‚ 7649548‚ 8673103‚ 11030304‚ 15517832‚ 11186939‚ 11186940‚ 16766665‚ 16841094‚ 18266238‚ 20624921‚ 21324899 Wilkie, A. O. M., Bochukova, E. G., (more...) Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006. Szabo, J., Bellus, G. A., Kaitila, (more...) Szabo, J., Bellus, G. A., Kaitila, I., Francomano, C. A. Fibroblast growth factor receptor 3 (FGFR3) mutations in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A287-only, 1996. Comment on evidence: In achondroplasia (100800), codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC … (more) In achondroplasia (100800), codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC (tyr). Rousseau et al. (1994) found the gly380-to-arg mutation in all 23 cases of achondroplasia studied (17 sporadic and 6 familial). Twenty-two of the 23 probands had the G-to-A transition; only 1 had the G-to-C transversion (134934.0002). See also Ikegawa et al. (1995). Nucleotide 1138 of the FGFR3 gene may be one of the most mutable bases in the human genome. Wilkie (1997) commented that it seems unlikely to be coincidental that the 3 highest germline point mutation rates described in the human (elevated approximately 1000-fold over background) all concern FGFRs: G380R and P250R in FGFR3 (134934.0014) and S252W in FGFR2 (176943.0010). These 3 mutations result in achondroplasia, Muenke nonsyndromic coronal craniosynostosis, and Apert syndrome (101200), respectively. Increased paternal age associated with achondroplasia and Apert syndrome has long been known, and an exclusively paternal origin of mutation was shown in studies of 57 Apert syndrome patients by Moloney et al. (1996) and in 10 achondroplasia patients by Szabo et al. (1996). In a 24-year-old woman whose fetus was suspected by ultrasonography to have a short-limb disorder, Saito et al. (2000) made the diagnosis of achondroplasia by identifying the 1138G-A mutation using PCR with specific primers. Restriction fragment length polymorphism analysis of PCR products was done with SfcI. DNA for the studies was extracted from maternal plasma; the mutation was not found in maternal leukocytes. Van Esch and Fryns (2004) described acanthosis nigricans in a 9-year-old boy with achondroplasia due to the classic gly380-to-arg mutation in FGFR3. Affected sibs with classic achondroplasia but unaffected parents were described by Henderson et al. (2000) and Sobetzko et al. (2000). Both were apparent instances of germinal mosaicism. In a sperm study of 97 men aged 22 to 80 years, Wyrobek et al. (2006) found associations between increased age and genomic defects as measured by the DNA fragmentation index and increased age and the FGFR3 1138G-A mutation without evidence for an age threshold. However, there was no association between age and frequency of sperm with immature chromatin, aneuploidies/diploidies, FGFR2 mutations causing Apert syndrome, or sex ratio. Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified mosaicism for a double mutation in exon 10 of the FGFR3 gene in 1 patient: the G372C mutation (G370C; 134934.0033) and the G382R mutation. Codons were numbered according to the FGFR3 IIIb isoform. In 3 sibs who were the product of the first and third pregnancies of healthy nonconsanguineous parents, Natacci et al. (2008) identified heterozygosity for the G380R mutation in the FGFR3 gene. The mutation was not found in lymphocytic DNA from the parents; however, DNA analysis of a sperm sample from the 37-year-old father showed the G380R mutation. The authors stated that this was the second reported case of germinal mosaicism causing recurrent achondroplasia in a subsequent conception. He et al. (2010) found that the G380R mutation within the transmembrane domain of FGFR3 increased the phosphorylation of tyr647 and tyr648 within the FGFR3 catalytic domain in the absence of FGF1 and at low FGF1 concentration. They determined that the increased kinase activity of mutant FGFR3 was due to a conformational change. The amino acids that mediate helix-helix contacts in the wildtype dimer are leu377, val381, phe384, and ile387, whereas the mutant dimer interface is rotated to involve ile376, arg380, phe383, ile387, val390, and thr394. The 2 alanines at position 391 face each other directly in the wildtype structure, but are rotated away from each other in the mutant structure. He et al. (2010) hypothesized that the rotation at the dimerization interface would induce a concomitant rotation of the catalytic domains with respect to each other and change their kinetics of kinase activity. He et al. (2011) showed that the G380R mutation decreased the probability of heterodimer formation between mutant and wildtype subunits at low ligand concentration, but not at high ligand concentration. (less)
Pathogenic (Oct 11, 2020)	no assertion criteria provided Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469248.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967748.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 29, 2022)	no assertion criteria provided Method: research	Achondroplasia Affected status: yes Allele origin: germline	Department of Genetics, Beijing BioBiggen Technology Co., Ltd. Accession: SCV002546558.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: Short fetal femur length (present) , Short lower limbs (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Short fetal femur length (present)
Pathogenic (Jun 18, 2018)	no assertion criteria provided Method: clinical testing	Achondroplasia Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000863902.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740638.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979494.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036538.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (Mar 16, 2022)	no assertion criteria provided Method: research	Achondroplasia Affected status: yes Allele origin: germline	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University Accession: SCV003844101.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Observation 1: Number of individuals with the variant: 1 Clinical Features: Short long bone (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Increased nuchal translucency (present) , Increased head circumference (present) , Short fetal femur length (present) , Short humerus (present) , shortened fibula (present) Observation 3: Number of individuals with the variant: 1 Clinical Features: Short femur (present) , Short humerus (present) Observation 4: Number of individuals with the variant: 1 Clinical Features: Short femur (present) , Short humerus (present) Observation 5: Number of individuals with the variant: 1 Clinical Features: Short femur (present) , Short humerus (present) Observation 6: Number of individuals with the variant: 1 Clinical Features: Fetal growth restriction (present)
Pathogenic (Feb 01, 2024)	no assertion criteria provided Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital Accession: SCV005045295.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Number of individuals with the variant: 1 Ethnicity/Population group: Asia Geographic origin: China
Pathogenic (Jul 08, 2024)	no assertion criteria provided Method: clinical testing	FGFR3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350704.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
not provided (-)	no classification provided Method: literature only	Hypochondroplasia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002318921.2 First in ClinVar: Apr 02, 2022 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1477 BookShelf: NBK1477 Comment: Common pathogenic variant in achondroplasia
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Citation text

Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006.

Citation text

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016327,VCV000016328, PMID:7913883,7913883, PS1_S). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23056398, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.696, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Hypochondroplasia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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].

Comment:

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

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Achondroplasia.	Adam MP	-	2023	PMID: 20301331
Molecular diagnosis for 55 fetuses with skeletal dysplasias by whole-exome sequencing: A retrospective cohort study.	Zhang L	Clinical genetics	2021	PMID: 33942288
Clinical application of medical exome sequencing for prenatal diagnosis of fetal structural anomalies.	Chen M	European journal of obstetrics, gynecology, and reproductive biology	2020	PMID: 32502767
Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management.	Han J	Prenatal diagnosis	2020	PMID: 31994750
Hypochondroplasia.	Adam MP	-	2020	PMID: 20301650
Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases.	Liu Y	Diagnostic pathology	2019	PMID: 31299979
Genetic Analysis in Fetal Skeletal Dysplasias by Trio Whole-Exome Sequencing.	Yang K	BioMed research international	2019	PMID: 31218223
Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.	Zhang J	Nature medicine	2019	PMID: 30692697
Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study.	Huang Z	Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology	2018	PMID: 30138938
Further delineation of achondroplasia-hypochondroplasia complex with long-term survival.	González-Del Angel A	American journal of medical genetics. Part A	2018	PMID: 29681095
[Rapid detection of hot spot mutations of FGFR3 gene with PCR-high resolution melting assay].	Li S	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2017	PMID: 28777845
Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia.	Lee YC	Scientific reports	2017	PMID: 28230213
Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?	Accogli A	American journal of medical genetics. Part A	2015	PMID: 25691418
FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.	Xue Y	Molecular genetics & genomic medicine	2014	DOI: 10.1002/mgg3.96
FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.	Xue Y	Molecular genetics & genomic medicine	2014	PMID: 25614871
A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly.	Makrythanasis P	Human mutation	2014	PMID: 24864036
Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies.	Bocharov EV	Structure (London, England : 1993)	2013	PMID: 24120763
Direct assessment of the effect of the Gly380Arg achondroplasia mutation on FGFR3 dimerization using quantitative imaging FRET.	Placone J	PloS one	2012	PMID: 23056398
Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.	Foldynova-Trantirkova S	Human mutation	2012	PMID: 22045636
Achondroplasia with synostosis of multiple sutures.	Georgoulis G	American journal of medical genetics. Part A	2011	PMID: 21739570
FGFR3 heterodimerization in achondroplasia, the most common form of human dwarfism.	He L	The Journal of biological chemistry	2011	PMID: 21324899
Physical basis behind achondroplasia, the most common form of human dwarfism.	He L	The Journal of biological chemistry	2010	PMID: 20624921
Germline mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs.	Natacci F	American journal of medical genetics. Part A	2008	PMID: 18266238
FGFR3 intracellular mutations induce tyrosine phosphorylation in the Golgi and defective glycosylation.	Gibbs L	Biochimica et biophysica acta	2007	PMID: 17320202
A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome.	Toydemir RM	American journal of human genetics	2006	PMID: 17033969
Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi.	Hafner C	The Journal of clinical investigation	2006	PMID: 16841094
Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm.	Wyrobek AJ	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16766665
Acanthosis nigricans in a boy with achondroplasia due to the classical Gly380Arg mutation in FGFR3.	Van Esch H	Genetic counseling (Geneva, Switzerland)	2004	PMID: 15517832
Achondroplasia with the FGFR3 1138g-->a (G380R) mutation in two sibs sharing a 4p haplotype derived from their unaffected father.	Sobetzko D	Journal of medical genetics	2000	PMID: 11186940
Germline and somatic mosaicism in achondroplasia.	Henderson S	Journal of medical genetics	2000	PMID: 11186939
Prenatal DNA diagnosis of a single-gene disorder from maternal plasma.	Saito H	Lancet (London, England)	2000	PMID: 11030304
Achondroplasia in diverse Jewish and Arab populations in Israel: clinical and molecular characterization.	Falik-Zaccai TC	The Israel Medical Association journal : IMAJ	2000	PMID: 10979354
Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice.	Segev O	Human molecular genetics	2000	PMID: 10607835
Exclusive paternal origin of new mutations in Apert syndrome.	Moloney DM	Nature genetics	1996	PMID: 8673103
Achondroplasia is defined by recurrent G380R mutations of FGFR3.	Bellus GA	American journal of human genetics	1995	PMID: 7847369
A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia.	Stoilov I	American journal of medical genetics	1995	PMID: 7702086
A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.	Bellus GA	Nature genetics	1995	PMID: 7670477
Mutations of the fibroblast growth factor receptor-3 gene in one familial and six sporadic cases of achondroplasia in Japanese patients.	Ikegawa S	Human genetics	1995	PMID: 7649548
Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.	Rousseau F	Nature	1994	PMID: 8078586
Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.	Shiang R	Cell	1994	PMID: 7913883
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3	-	-	-	-
Szabo, J., Bellus, G. A., Kaitila, I., Francomano, C. A. Fibroblast growth factor receptor 3 (FGFR3) mutations in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A287-only, 1996.	-	-	-	-
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Text-mined citations for rs28931614 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28931614 ...