ClinVar Genomic variation as it relates to human health
NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu)
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.
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.
Uncertain significance(4); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu)
Variation ID: 549484 Accession: VCV000549484.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.13 10: 121520163 (GRCh38) [ NCBI UCSC ] 10: 123279677 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 21, 2018 Apr 15, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000141.5:c.755C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000132.3:p.Ser252Leu missense NM_022970.4:c.755C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_075259.4:p.Ser252Leu missense NM_001144913.1:c.755C>T NP_001138385.1:p.Ser252Leu missense NM_001144914.1:c.749-4844C>T intron variant NM_001144915.2:c.488C>T NP_001138387.1:p.Ser163Leu missense NM_001144916.2:c.410C>T NP_001138388.1:p.Ser137Leu missense NM_001144917.2:c.755C>T NP_001138389.1:p.Ser252Leu missense NM_001144918.2:c.410C>T NP_001138390.1:p.Ser137Leu missense NM_001144919.2:c.488C>T NP_001138391.1:p.Ser163Leu missense NM_001320654.2:c.71C>T NP_001307583.1:p.Ser24Leu missense NM_001320658.2:c.755C>T NP_001307587.1:p.Ser252Leu missense NM_022969.1:c.755C>T NP_075258.1:p.Ser252Leu missense NM_023029.2:c.488C>T NP_075418.1:p.Ser163Leu missense NR_073009.2:n.1043C>T non-coding transcript variant NC_000010.11:g.121520163G>A NC_000010.10:g.123279677G>A NG_012449.2:g.83296C>T LRG_994:g.83296C>T LRG_994t1:c.755C>T LRG_994p1:p.Ser252Leu LRG_994t2:c.755C>T LRG_994p2:p.Ser252Leu - Protein change
- S252L, S24L, S137L, S163L
- Other names
- NM_000141.4:c.755C>T(p.Ser252Leu)
- NM_001144913.1:c.755C>T(p.Ser252Leu)
- NM_001144915.1:c.488C>T(p.Ser163Leu)
- NM_001144916.1:c.410C>T(p.Ser137Leu)
- NM_001144917.1:c.755C>T(p.Ser252Leu)
- NM_001144918.1:c.410C>T(p.Ser137Leu)
- NM_001144919.1:c.488C>T(p.Ser163Leu)
- NM_022970.3:c.755C>T(p.Ser252Leu)
- NM_023029.2:c.488C>T(p.Ser163Leu)
- Canonical SPDI
- NC_000010.11:121520162:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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FGFR2 | - | - |
GRCh38 GRCh37 |
731 | 783 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2020 | RCV000664049.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 28, 2023 | RCV001313539.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 1, 2023 | RCV002298724.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 4, 2022 | RCV003403529.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003987651.1 |
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
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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
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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
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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. |
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Benign
(Apr 16, 2018)
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criteria provided, single submitter
Method: curation
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Crouzon syndrome
Affected status: unknown
Allele origin:
germline
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SIB Swiss Institute of Bioinformatics
Accession: SCV000787470.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
Comment:
This variant is interpreted as a Benign, for Crouzon syndrome, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in … (more)
This variant is interpreted as a Benign, for Crouzon syndrome, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:9002682). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:9002682). (less)
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138181.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Jun 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001430659.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
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Uncertain significance
(Oct 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002588317.2
First in ClinVar: Nov 05, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported in individuals with Crouzon syndrome, inherited from apparently unaffected parents (Oldridge et al., 1997; Ohishi et al., 2017); Reported in a family where affected … (more)
Reported in individuals with Crouzon syndrome, inherited from apparently unaffected parents (Oldridge et al., 1997; Ohishi et al., 2017); Reported in a family where affected members had severe syndactyly without craniosynostosis and harbored a second FGFR2 variant in cis with p.(S252L) (Wilkie et al., 2002).; 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: 15282208, 15840724, 9700203, 26003532, 17621648, 9300656, 27683237, 32908727, 31348830, 9002682, 12357470, 29037998, 20301628) (less)
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Uncertain significance
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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FGFR2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105740.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FGFR2 c.755C>T variant is predicted to result in the amino acid substitution p.Ser252Leu. This variant has been reported in several individuals with Crouzon syndrome, … (more)
The FGFR2 c.755C>T variant is predicted to result in the amino acid substitution p.Ser252Leu. This variant has been reported in several individuals with Crouzon syndrome, but it has also been observed in clinically normal members with the families (Oldridge et al 1997. PubMed ID: 9002682; Sakai N et al 2001. PubMed ID: 11711827; Ohishi et al. 2016. PbuMed ID: 27683237). In one study, functional analysis of this variant revealed wild-type kinetic (Anderson J et al 1998. PubMed ID: 9700203). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-123279677-G-A). A different substitution affecting the same amino acid (p.Ser252Trp) has been reported in association with Apert syndrome (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jan 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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FGFR2-related craniosynostosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001504038.3
First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is … (more)
This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is present in population databases (rs79184941, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 252 of the FGFR2 protein (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 549484). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser252 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FGFR2 function (PMID: 9700203). 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. (less)
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Uncertain significance
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804229.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: FGFR2 c.755C>T (p.Ser252Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: FGFR2 c.755C>T (p.Ser252Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. c.755C>T has been reported in the literature in two independent families affected with Crouzon syndrome and the variant was present in both affected individuals as well as clinically normal family members (examples: Oldridge_1997, Oshini_2017). Additionally, this variant was seen in cis with a second pathogenic variant in a mother and her daughter affected with syndactyly (Wilkie_2002). At least one publication reports experimental evidence that FGFR2 mutant Ser252Leu exhibited kinetic behavior identical to wild-type (Anderson_1998). These data suggest a benign role for this variant however, other variants affecting this residue have been classified pathogenic/likely pathogenic in ClinVar (CV IDs: 13272, 13279). ClinVar contains an entry for this variant (Variation ID: 549484). The following publications have been ascertained in the context of this evaluation (PMID: 9002682, 9700203, 15282208, 11711827, 27683237, 12357470). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jan 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004134775.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
FGFR2: BS1
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations in the FGFR2 gene in Mexican patients with Apert syndrome. | Ibarra-Arce A | Genetics and molecular research : GMR | 2015 | PMID: 25867380 |
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 |
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 |
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 |
Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. | Ibrahimi OA | Human molecular genetics | 2004 | PMID: 15282208 |
FGFs, their receptors, and human limb malformations: clinical and molecular correlations. | Wilkie AO | American journal of medical genetics | 2002 | PMID: 12357470 |
Sequence analysis of fibroblast growth factor receptor 2 ( FGFR2 ) in Japanese patients with craniosynostosis. | Sakai N | The Journal of craniofacial surgery | 2001 | PMID: 11711827 |
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 |
Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. | Anderson J | Human molecular genetics | 1998 | PMID: 9700203 |
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 |
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Text-mined citations for rs79184941 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.