VCV000013272.66 - ClinVar

NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp)

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.

(40)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp)

Variation ID: 13272 Accession: VCV000013272.66

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.13 10: 121520163 (GRCh38) [ NCBI UCSC ] 10: 123279677 (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	Jan 31, 2016	Oct 20, 2024	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000141.5:c.755C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000132.3:p.Ser252Trp	missense
NM_022970.4:c.755C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075259.4:p.Ser252Trp	missense
NM_000141.4:c.[755C>G]		missense
NM_001144913.1:c.755C>G	NP_001138385.1:p.Ser252Trp	missense
NM_001144914.1:c.749-4844C>G		intron variant
NM_001144915.2:c.488C>G	NP_001138387.1:p.Ser163Trp	missense
NM_001144916.2:c.410C>G	NP_001138388.1:p.Ser137Trp	missense
NM_001144917.2:c.755C>G	NP_001138389.1:p.Ser252Trp	missense
NM_001144918.2:c.410C>G	NP_001138390.1:p.Ser137Trp	missense
NM_001144919.2:c.488C>G	NP_001138391.1:p.Ser163Trp	missense
NM_001320654.2:c.71C>G	NP_001307583.1:p.Ser24Trp	missense
NM_001320658.2:c.755C>G	NP_001307587.1:p.Ser252Trp	missense
NM_022969.1:c.755C>G	NP_075258.1:p.Ser252Trp	missense
NM_023029.2:c.488C>G	NP_075418.1:p.Ser163Trp	missense
NR_073009.2:n.1043C>G		non-coding transcript variant
NC_000010.11:g.121520163G>C
NC_000010.10:g.123279677G>C
NG_012449.2:g.83296C>G
LRG_994:g.83296C>G
LRG_994t1:c.755C>G	LRG_994p1:p.Ser252Trp
LRG_994t2:c.755C>G	LRG_994p2:p.Ser252Trp
	P21802:p.Ser252Trp

... more HGVS ... less HGVS

Protein change

S252W, S137W, S163W, S24W

Other names

Canonical SPDI

NC_000010.11:121520162:G:C

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.

Links

ClinGen: CA122985 UniProtKB: P21802#VAR_004115 OMIM: 176943.0010 dbSNP: rs79184941 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.
FGFR2		-	-	GRCh38 GRCh37	767	821

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.
Acrocephalosyndactyly type I	Pathogenic (18)	criteria provided, multiple submitters, no conflicts	Jun 7, 2024	RCV000014191.55
Endometrial carcinoma	Pathogenic (1)	no assertion criteria provided	Nov 1, 2007	RCV000014192.13
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Feb 16, 2024	RCV000263144.42
Malignant neoplasm of body of uterus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422979.9
Uterine carcinosarcoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433250.9
Endometrium neoplasm	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000438603.9
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440715.9
FGFR2-related craniosynostosis	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 30, 2023	RCV000552015.20
Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation	Likely pathogenic (1)	no assertion criteria provided	Dec 26, 2014	RCV000431027.9
Acrocephalosyndactyly	Likely pathogenic (1)	no assertion criteria provided	May 13, 2016	RCV000433942.9
Acrocephalosyndactyly type I Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Beare-Stevenson cutis gyrata syndrome Bent bone dysplasia syndrome 1 Crouzon syndrome Familial scaphocephaly syndrome, McGillivray type Gastric cancer Jackson-Weiss syndrome Levy-Hollister syndrome Pfeiffer syndrome Saethre-Chotzen syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 12, 2021	RCV002476961.8
Pfeiffer syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004527288.2
FGFR2-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV004532334.2
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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 (Apr 01, 2015)	criteria provided, single submitter (Submitter's publication) Method: research	Apert syndrome Affected status: yes Allele origin: germline	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília Accession: SCV000223905.1 First in ClinVar: Jan 31, 2016 Last updated: Jan 31, 2016	Publications: PubMed (1) PubMed: 26380986 Geographic origin: Brazil
Pathogenic (Sep 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Apert syndrome Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448735.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FGFR2-related craniosynostosis Affected status: yes Allele origin: germline	DASA Accession: SCV002061183.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (10) PubMed: 24489893‚ 25867380‚ 26380986‚ 31145570‚ 14695532‚ 14972326‚ 24016645‚ 23787031‚ 23632174‚ 23430493 Comment: The c.755C>G;p.(Ser252Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13272; PMID: 24489893; 25867380; 26380986; … (more) The c.755C>G;p.(Ser252Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13272; PMID: 24489893; 25867380; 26380986; 31145570) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24489893) - PS3_moderate. This variant is not present in population databases (rs79184941, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in FGFR2 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073300.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: The missense variant p.S252W in FGFR2 (NM_000141.4) has been previously reported as a common mutation in Apert Syndrome (Polla D et al, 2015). Functional studies … (more) The missense variant p.S252W in FGFR2 (NM_000141.4) has been previously reported as a common mutation in Apert Syndrome (Polla D et al, 2015). Functional studies demonstrate a constituional activation of FGFR2 (Ibrahimi et al, 2001). The variant has been submitted to ClinVar as Pathogenic. The missense variant c.755C>G (p.S252W) in FGFR2 (NM_000141.5) is observed in 1/16152 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict a damaging effect and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Polydactyly of a biphalangeal thumb (present) , Postaxial hand polydactyly (present) , Posterior fossa cyst (present) , Corpus callosum, agenesis of (present) , Intellectual disability … (more) Polydactyly of a biphalangeal thumb (present) , Postaxial hand polydactyly (present) , Posterior fossa cyst (present) , Corpus callosum, agenesis of (present) , Intellectual disability (present) , Abnormal morphology of the limbic system (present) , Megalencephaly (present) , Cryptorchidism (present) , Absent septum pellucidum (present) , Autosomal dominant inheritance (present) , Overriding aorta (present) , Narrow palate (present) , Bifid uvula (present) , Cleft palate (present) , Vaginal atresia (present) , Hydronephrosis (present) , Congenital hypertrophic pyloric stenosis (present) , Esophageal atresia (present) , Cervical C5/C6 vertebrae fusion (present) , Midface retrusion (present) , Broad distal hallux (present) , Ventriculomegaly (present) , Cutaneous finger syndactyly (present) , Arachnoid cyst (present) , Broad distal phalanx of the thumb (present) , Chiari type I malformation (present) , Acne (present) , Delayed eruption of teeth (present) , Dental malocclusion (present) , Ectopic anus (present) , Humeroradial synostosis (present) , Coronal craniosynostosis (present) , Acrobrachycephaly (present) , Anomalous tracheal cartilage (present) , Delayed cranial suture closure (present) , Malar flattening (present) , Synostosis of carpal bones (present) , Brachyturricephaly (present) , Large fontanelles (present) , Hydrocephalus (present) , Growth abnormality (present) , Flat face (present) , Chronic otitis media (present) , Hearing impairment (present) , Broad forehead (present) , High forehead (present) , Hypertelorism (present) , Ventricular septal defect (present) , Mandibular prognathia (present) , Depressed nasal bridge (present) , Strabismus (present) , Downslanted palpebral fissures (present) , Choanal atresia (present) , Choanal stenosis (present) , Shallow orbits (present) (less)
Pathogenic (Feb 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525629.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: This is a recurrent pathogenic variant that has previously been reported in several unrelated individuals with Apert syndrome and other FGFR2-associated craniosynostosis syndromes (NBK541728). It … (more) This is a recurrent pathogenic variant that has previously been reported in several unrelated individuals with Apert syndrome and other FGFR2-associated craniosynostosis syndromes (NBK541728). It is one of the most commonly detected variants in individuals with Apert syndrome accounting for approximately 60-70% of cases (NBK541728). This variant has been observed in one individual in the Genome Aggregation Database (1 of 249,864 alleles; v2.1.1). The c.755C>G variant is predicted to replace the serine at codon 252 with tryptophan and experimentally shown to result in a gain of function of FGFR2 (PMID: 9700203). (less) Clinical Features: Toe syndactyly (present) , Finger syndactyly (present) , Cranial asymmetry (present) , Shallow orbits (present) , Hypertelorism (present) , Cleft palate (present) , Craniosynostosis syndrome … (more) Toe syndactyly (present) , Finger syndactyly (present) , Cranial asymmetry (present) , Shallow orbits (present) , Hypertelorism (present) , Cleft palate (present) , Craniosynostosis syndrome (present) , Synostosis involving bones of the toes (present) (less)
Pathogenic (Jul 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580222.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PS3, PS4, PM2_SUP, PP3	Number of individuals with the variant: 1
Pathogenic (Aug 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Saethre-Chotzen syndrome Pfeiffer syndrome Jackson-Weiss syndrome Crouzon syndrome Beare-Stevenson cutis gyrata syndrome LADD syndrome 1 Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Familial scaphocephaly syndrome, McGillivray type Gastric cancer Bent bone dysplasia syndrome 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893154.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807349.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP1 supporting, PP3 supporting Observation 1: Number of individuals with the variant: 1 Clinical Features: 2-4 finger cutaneous syndactyly (present) , Choanal atresia (present) , Microcephaly (present) , Abnormal facial shape (present) , Facial asymmetry (present) , Mandibular prognathia (present) … (more) 2-4 finger cutaneous syndactyly (present) , Choanal atresia (present) , Microcephaly (present) , Abnormal facial shape (present) , Facial asymmetry (present) , Mandibular prognathia (present) , Plagiocephaly (present) , Craniosynostosis syndrome (present) , Decreased body weight (present) , Multiple suture craniosynostosis (present) , Neonatal respiratory distress (present) , Proptosis (present) , Osseous syndactyly of toes (present) , Toe syndactyly (present) , Osseous finger syndactyly (present) , 2-3 finger cutaneous syndactyly (present) , 2-5 toe syndactyly (present) , Macrotia (present) , Finger syndactyly (present) , Hypertelorism (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing Observation 2: Number of individuals with the variant: 1 Clinical Features: Epicanthus (present) , Craniosynostosis syndrome (present) , Syndactyly (present) , Brachycephaly (present) , Small face (present) , Hypertelorism (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Jun 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: de novo	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam Accession: SCV003934959.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Number of individuals with the variant: 1 Geographic origin: Vietnam
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	FGFR2-related craniosynostosis Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004123087.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Aug 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	FGFR2-related craniosynostosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659618.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 11390973‚ 22664175‚ 23495007‚ 24489893‚ 7719344‚ 8651276‚ 9462761‚ 25867380 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 13272). This missense change has been observed in individual(s) with Apert syndrome, accounting for disease in approximately 71% of affected individuals and families (PMID: 7719344, 8651276, 9462761, 25867380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs79184941, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the FGFR2 protein (p.Ser252Trp). (less)
Pathogenic (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Acrocephalosyndactyly type I Affected status: unknown Allele origin: germline	SIB Swiss Institute of Bioinformatics Accession: SCV000883242.1 First in ClinVar: Aug 13, 2018 Last updated: Aug 13, 2018	Publications: PubMed (4) PubMed: 14499350‚ 24489893‚ 15975938‚ 23546041 Comment: This variant is interpreted as Pathogenic, for Apert syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support … (more) This variant is interpreted as Pathogenic, for Apert syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/14499350) (https://www.ncbi.nlm.nih.gov/pubmed/24489893) (https://www.ncbi.nlm.nih.gov/pubmed/15975938). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/23546041). (less)
Pathogenic (Mar 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000925947.1 First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019	Publications: PubMed (3) PubMed: 20301628‚ 11121055‚ 11390973 Comment: This FGFR2 variant (rs79184941) has been identified in 71% of patients with Apert syndrome and is rare in large population datasets (gnomAD: 1/249864 total alleles; … (more) This FGFR2 variant (rs79184941) has been identified in 71% of patients with Apert syndrome and is rare in large population datasets (gnomAD: 1/249864 total alleles; 0.0004%; no homozygotes). It has been reported as an assumed de novo variant and has been shown to segregate with disease in multiple families. Six submitters in ClinVar classify FGFR2 c.755C>G as pathogenic. Functional studies have demonstrated that this variant shows a gain-of-function effect by enhancing FGFR2 ligand binding affinity. This variant is considered pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV001437545.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Number of individuals with the variant: 9 Clinical Features: Craniosynostosis (present)
Pathogenic (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832423.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (Sep 17, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Apert syndrome Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000328367.2 First in ClinVar: Jan 31, 2016 Last updated: Mar 04, 2023 Comment: Clinical Testing	Number of individuals with the variant: 21
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: unknown	3billion Accession: SCV003841499.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 7719344‚ 9002682 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013272 / PMID: 7719344 / 3billion dataset). A different missense change at the same codon (p.Ser252Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013279 / PMID: 9002682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Brachycephaly (present) , Hypertelorism (present) , Anodontia (present) , Finger syndactyly (present) , Toe syndactyly (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FGFR2-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046053.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been previously reported as a heterozygous change in individuals with Apert syndrome (PMID: 7719344, 8651276, 9462761, 25867380). It is present in the … (more) This variant has been previously reported as a heterozygous change in individuals with Apert syndrome (PMID: 7719344, 8651276, 9462761, 25867380). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/249864). The c.755C>G (p.Ser252Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.755C>G (p.Ser252Trp) variant is classified as Pathogenic. (less)
Pathogenic (Oct 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023062.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pfeiffer syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005038841.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024
Pathogenic (Jul 13, 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: SCV005197922.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088771.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant has been reported as a recurrent variant in Apert syndrome, accounting for disease in approximately 71% of affected individuals and families. It segregates … (more) This variant has been reported as a recurrent variant in Apert syndrome, accounting for disease in approximately 71% of affected individuals and families. It segregates with the disease in several families with multiple affected individuals [PMID: 7719344, 8651276, 25867380, 9462761, 12124745, 23546041]. Functionall studies have shown that the variant exerts a gain-of-function effect by enhancing FGFR2 binding affinity [PMID: 11390973, 22664175, 23495007, 24489893]. (less)
Pathogenic (Feb 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329832.9 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect resulting in altered receptor affinity and upregulation of FGF signaling leading … (more) Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect resulting in altered receptor affinity and upregulation of FGF signaling leading to the dysregulation of genes involved in bone formation, bone mineralization and osteoclastogenesis (PMID: 23519026, 9700203, 24489893, 31064775); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31879841, 28316926, 16440883, 19186770, 31387623, 34367232, 7719344, 23754559, 23495007, 22664175, 25867380, 9700203, 22105374, 10067911, 23593218, 24489893, 25297884, 9462761, 22048896, 23546041, 21154333, 25045033, 25433548, 27228464, 18215098, 28976722, 16951439, 29483804, 8651276, 30355600, 29753329, 30656008, 15282208, 30679815, 9719378, 16906598, 29037998, 30657466, 31064775, 30719288, 31502745, 30672749, 31837199, 31019026, 32954549, 10658283, 32510873, 8676562, 33937142, 35088901, 35591945, 33585639, 34958143, 34358384, 34094714, 31145570, 23519026) (less)
Pathogenic (Jun 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrocephalosyndactyly type I (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368082.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PS2,PS4,PS3_MOD,PM2_MOD,PP3 Clinical Features: Focal-onset seizure (present) Sex: female
Pathogenic (May 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: SCV001247453.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: FGFR2: PS2, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting Number of individuals with the variant: 3
Pathogenic (Nov 01, 2007)	no assertion criteria provided Method: literature only	APERT SYNDROME Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000034439.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2018	Publications: PubMed (6) PubMed: 12124745‚ 8651276‚ 9719378‚ 16440883‚ 11390973‚ 17525745 Comment on evidence: In 25 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp … (more) In 25 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp (S252W) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The mutation occurs within a CpG dinucleotide and is adjacent to another FGFR2 mutation causing Apert syndrome (P253R; 176943.0011), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. Among 70 unrelated patients with Apert syndrome, Slaney et al. (1996) found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. Slaney et al. (1996) suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. Passos-Bueno et al. (1998) reported a child whom they identified as having a Pfeiffer syndrome (101600)-like phenotype, without severe abnormalities of the upper and lower extremities, who had the S252W mutation. Mantilla-Capacho et al. (2005) reported a patient with Apert syndrome caused by the S252W mutation, which they stated resulted from a 755C-G transversion. The child did not have cleft palate, but did have preaxial polydactyly of the hands and feet. By analysis of crystal structure, Ibrahimi et al. (2001) showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. Pollock et al. (2007) identified a somatic S252W mutation in 8 of 187 samples of endometrial carcinoma (608089), 7 of which were the endometrioid subtype and 1 of which was the serous subtype. It was the most common FGFR2 mutation identified. (less)
Pathogenic (Nov 01, 2007)	no assertion criteria provided Method: literature only	ENDOMETRIAL CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000034440.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2018	Publications: PubMed (6) PubMed: 12124745‚ 8651276‚ 9719378‚ 16440883‚ 11390973‚ 17525745 Comment on evidence: In 25 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp … (more) In 25 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp (S252W) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The mutation occurs within a CpG dinucleotide and is adjacent to another FGFR2 mutation causing Apert syndrome (P253R; 176943.0011), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. Among 70 unrelated patients with Apert syndrome, Slaney et al. (1996) found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. Slaney et al. (1996) suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. Passos-Bueno et al. (1998) reported a child whom they identified as having a Pfeiffer syndrome (101600)-like phenotype, without severe abnormalities of the upper and lower extremities, who had the S252W mutation. Mantilla-Capacho et al. (2005) reported a patient with Apert syndrome caused by the S252W mutation, which they stated resulted from a 755C-G transversion. The child did not have cleft palate, but did have preaxial polydactyly of the hands and feet. By analysis of crystal structure, Ibrahimi et al. (2001) showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. Pollock et al. (2007) identified a somatic S252W mutation in 8 of 187 samples of endometrial carcinoma (608089), 7 of which were the endometrioid subtype and 1 of which was the serous subtype. It was the most common FGFR2 mutation identified. (less)
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: SCV001971109.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 29, 2022)	no assertion criteria provided Method: research	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Department of Genetics, Beijing BioBiggen Technology Co., Ltd. Accession: SCV002540763.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Clinical Features: abnormal skull: bilateral fingers and toes (present)
Likely pathogenic (Dec 26, 2014)	no assertion criteria provided Method: literature only	Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504809.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 18552176‚ 23002168‚ 22238366 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000457416:c.755C>G
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Endometrium neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504810.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 21367659 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000457416:c.755C>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant neoplasm of body of uterus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506414.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000351936:c.755C>G
Likely pathogenic (May 13, 2016)	no assertion criteria provided Method: literature only	Acrocephalosyndactyly (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506412.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 10851026 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000351936:c.755C>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506413.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000351936:c.755C>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Uterine carcinosarcoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506415.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000351936:c.755C>G
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) Study: VKGL Data-share Consensus Accession: SCV001798214.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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: SCV001956035.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Sep 16, 2021)	no assertion criteria provided Method: research	Acrocephalosyndactyly type I Affected status: yes Allele origin: germline	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University Accession: SCV003844078.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Clinical Features: Syndactyly (present)
Pathogenic (Jan 13, 2024)	no assertion criteria provided Method: clinical testing	FGFR2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004736613.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The FGFR2 c.755C>G variant is predicted to result in the amino acid substitution p.Ser252Trp. This variant is the most common recurrent variant reported in patients … (more) The FGFR2 c.755C>G variant is predicted to result in the amino acid substitution p.Ser252Trp. This variant is the most common recurrent variant reported in patients with Apert syndrome (Wilkie et al. 1995. PubMed ID: 7719344, reported as c.934C>G; Passos-Bueno et al. 1998. PubMed ID: 9719378; Polla et al. 2015. PubMed ID: 26380986; Kunwar et al. 2017. PubMed ID: 28316926). The variant is observed once in population databases indicating this variant is rare. In summary, this variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Acrocephalosyndactyly type I Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000929990.2 First in ClinVar: Jul 31, 2019 Last updated: Oct 01, 2022 Comment: Originally published as C934G [Wilkie et al 1995]	Publications: PubMed (2) PubMed: 31145570‚ 7719344 BookShelf: NBK541728 BookShelf: NBK541728
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Comment:

The c.755C>G;p.(Ser252Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13272; PMID: 24489893; 25867380; 26380986; 31145570) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24489893) - PS3_moderate. This variant is not present in population databases (rs79184941, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in FGFR2 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. 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:

The missense variant p.S252W in FGFR2 (NM_000141.4) has been previously reported as a common mutation in Apert Syndrome (Polla D et al, 2015). Functional studies demonstrate a constituional activation of FGFR2 (Ibrahimi et al, 2001). The variant has been submitted to ClinVar as Pathogenic. The missense variant c.755C>G (p.S252W) in FGFR2 (NM_000141.5) is observed in 1/16152 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict a damaging effect and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.

Comment:

This is a recurrent pathogenic variant that has previously been reported in several unrelated individuals with Apert syndrome and other FGFR2-associated craniosynostosis syndromes (NBK541728). It is one of the most commonly detected variants in individuals with Apert syndrome accounting for approximately 60-70% of cases (NBK541728). This variant has been observed in one individual in the Genome Aggregation Database (1 of 249,864 alleles; v2.1.1). The c.755C>G variant is predicted to replace the serine at codon 252 with tryptophan and experimentally shown to result in a gain of function of FGFR2 (PMID: 9700203).

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 13272). This missense change has been observed in individual(s) with Apert syndrome, accounting for disease in approximately 71% of affected individuals and families (PMID: 7719344, 8651276, 9462761, 25867380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs79184941, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the FGFR2 protein (p.Ser252Trp).

Comment:

This variant is interpreted as Pathogenic, for Apert syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/14499350) (https://www.ncbi.nlm.nih.gov/pubmed/24489893) (https://www.ncbi.nlm.nih.gov/pubmed/15975938). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/23546041).

Comment:

This FGFR2 variant (rs79184941) has been identified in 71% of patients with Apert syndrome and is rare in large population datasets (gnomAD: 1/249864 total alleles; 0.0004%; no homozygotes). It has been reported as an assumed de novo variant and has been shown to segregate with disease in multiple families. Six submitters in ClinVar classify FGFR2 c.755C>G as pathogenic. Functional studies have demonstrated that this variant shows a gain-of-function effect by enhancing FGFR2 ligand binding affinity. This variant is considered pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013272 / PMID: 7719344 / 3billion dataset). A different missense change at the same codon (p.Ser252Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013279 / PMID: 9002682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant has been previously reported as a heterozygous change in individuals with Apert syndrome (PMID: 7719344, 8651276, 9462761, 25867380). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/249864). The c.755C>G (p.Ser252Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.755C>G (p.Ser252Trp) variant is classified as Pathogenic.

Comment:

This variant has been reported as a recurrent variant in Apert syndrome, accounting for disease in approximately 71% of affected individuals and families. It segregates with the disease in several families with multiple affected individuals [PMID: 7719344, 8651276, 25867380, 9462761, 12124745, 23546041]. Functionall studies have shown that the variant exerts a gain-of-function effect by enhancing FGFR2 binding affinity [PMID: 11390973, 22664175, 23495007, 24489893].

Comment:

Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect resulting in altered receptor affinity and upregulation of FGF signaling leading to the dysregulation of genes involved in bone formation, bone mineralization and osteoclastogenesis (PMID: 23519026, 9700203, 24489893, 31064775); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31879841, 28316926, 16440883, 19186770, 31387623, 34367232, 7719344, 23754559, 23495007, 22664175, 25867380, 9700203, 22105374, 10067911, 23593218, 24489893, 25297884, 9462761, 22048896, 23546041, 21154333, 25045033, 25433548, 27228464, 18215098, 28976722, 16951439, 29483804, 8651276, 30355600, 29753329, 30656008, 15282208, 30679815, 9719378, 16906598, 29037998, 30657466, 31064775, 30719288, 31502745, 30672749, 31837199, 31019026, 32954549, 10658283, 32510873, 8676562, 33937142, 35088901, 35591945, 33585639, 34958143, 34358384, 34094714, 31145570, 23519026)

Comment:

The FGFR2 c.755C>G variant is predicted to result in the amino acid substitution p.Ser252Trp. This variant is the most common recurrent variant reported in patients with Apert syndrome (Wilkie et al. 1995. PubMed ID: 7719344, reported as c.934C>G; Passos-Bueno et al. 1998. PubMed ID: 9719378; Polla et al. 2015. PubMed ID: 26380986; Kunwar et al. 2017. PubMed ID: 28316926). The variant is observed once in population databases indicating this variant is rare. In summary, 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
FGFR Craniosynostosis Syndromes Overview.	Adam MP	-	2020	PMID: 20301628
Apert Syndrome.	Adam MP	-	2019	PMID: 31145570
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders.	Polla DL	PloS one	2015	PMID: 26380986
Mutations in the FGFR2 gene in Mexican patients with Apert syndrome.	Ibarra-Arce A	Genetics and molecular research : GMR	2015	PMID: 25867380
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
A Ser252Trp mutation in fibroblast growth factor receptor 2 (FGFR2) mimicking human Apert syndrome reveals an essential role for FGF signaling in the regulation of endochondral bone formation.	Chen P	PloS one	2014	PMID: 24489893
[Juvenile Pompe disease: retrospective clinical study].	Loureiro Neves F	Acta medica portuguesa	2013	PMID: 24016645
Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy.	Prater SN	Orphanet journal of rare diseases	2013	PMID: 23787031
Alkaptonuria and Pompe disease in one patient: metabolic and molecular analysis.	Zouheir Habbal M	BMJ case reports	2013	PMID: 23632174
p.Ser252Trp and p.Pro253Arg mutations in FGFR2 gene causing Apert syndrome: the first clinical and molecular report of Indonesian patients.	Mundhofir FE	Singapore medical journal	2013	PMID: 23546041
The Fgfr2(S252W/+) mutation in mice retards mandible formation and reduces bone mass as in human Apert syndrome.	Zhou X	American journal of medical genetics. Part A	2013	PMID: 23495007
Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease.	Niño MY	JIMD reports	2013	PMID: 23430493
FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor.	Guagnano V	Cancer discovery	2012	PMID: 23002168
Mesodermal expression of Fgfr2S252W is necessary and sufficient to induce craniosynostosis in a mouse model of Apert syndrome.	Holmes G	Developmental biology	2012	PMID: 22664175
Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models.	Gozgit JM	Molecular cancer therapeutics	2012	PMID: 22238366
Targeting mutant fibroblast growth factor receptors in cancer.	Greulich H	Trends in molecular medicine	2011	PMID: 21367659
Drug-sensitive FGFR2 mutations in endometrial carcinoma.	Dutt A	Proceedings of the National Academy of Sciences of the United States of America	2008	PMID: 18552176
Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.	Pollock PM	Oncogene	2007	PMID: 17525745
Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene.	Mantilla-Capacho JM	Genetic counseling (Geneva, Switzerland)	2005	PMID: 16440883
Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse.	Wang Y	Development (Cambridge, England)	2005	PMID: 15975938
Glycogenosis type II: identification and expression of three novel mutations in the acid alpha-glucosidase gene causing the infantile form of the disease.	Montalvo AL	Molecular genetics and metabolism	2004	PMID: 14972326
Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.	Hermans MM	Human mutation	2004	PMID: 14695532
A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis.	Chen L	Bone	2003	PMID: 14499350
Abnormal spliceform expression associated with splice acceptor mutations in exon IIIc of FGFR2.	Wilkie AO	American journal of medical genetics	2002	PMID: 12124745
Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.	Ibrahimi OA	Proceedings of the National Academy of Sciences of the United States of America	2001	PMID: 11390973
Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.	Yu K	Proceedings of the National Academy of Sciences of the United States of America	2000	PMID: 11121055
Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts.	Mansukhani A	The Journal of cell biology	2000	PMID: 10851026
Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly.	Passos-Bueno MR	Journal of medical genetics	1998	PMID: 9719378
Mutation of the fibroblast growth factor receptor 2 gene in Japanese patients with Apert syndrome.	Matsumoto K	Plastic and reconstructive surgery	1998	PMID: 9462761
Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.	Oldridge M	Human molecular genetics	1997	PMID: 9002682
Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.	Slaney SF	American journal of human genetics	1996	PMID: 8651276
Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.	Wilkie AO	Nature genetics	1995	PMID: 7719344
http://docm.genome.wustl.edu/variants/ENST00000351936:c.755C>G	-	-	-	-
http://docm.genome.wustl.edu/variants/ENST00000457416:c.755C>G	-	-	-	-
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Text-mined citations for rs79184941 ...

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_000141.5(FGFR2):c.755C>G (p.Ser252Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs79184941 ...