ACMG codes: PS3; PS4; PM2; PP1; PP3; PP5
ClinVar Genomic variation as it relates to human health
NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)
Germline
Classification
Help
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.
(10)
Help
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)
Variation ID: 16279 Accession: VCV000016279.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p11.23 8: 38424690 (GRCh38) [ NCBI UCSC ] 8: 38282208 (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 Aug 15, 2015 Oct 20, 2024 Mar 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_023110.3:c.755C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_075598.2:p.Pro252Arg missense NM_001174063.2:c.755C>G NP_001167534.1:p.Pro252Arg missense NM_001174064.2:c.731C>G NP_001167535.1:p.Pro244Arg missense NM_001174065.2:c.749C>G NP_001167536.1:p.Pro250Arg missense NM_001174066.2:c.488C>G NP_001167537.1:p.Pro163Arg missense NM_001174067.2:c.848C>G NP_001167538.1:p.Pro283Arg missense NM_001354367.2:c.749C>G NP_001341296.1:p.Pro250Arg missense NM_001354368.2:c.482C>G NP_001341297.1:p.Pro161Arg missense NM_001354369.2:c.749C>G NP_001341298.1:p.Pro250Arg missense NM_001354370.2:c.482C>G NP_001341299.1:p.Pro161Arg missense NM_015850.4:c.749C>G NP_056934.2:p.Pro250Arg missense NM_023105.3:c.488C>G NP_075593.1:p.Pro163Arg missense NM_023106.3:c.482C>G NP_075594.1:p.Pro161Arg missense NC_000008.11:g.38424690G>C NC_000008.10:g.38282208G>C NG_007729.1:g.49145C>G LRG_993:g.49145C>G LRG_993t1:c.755C>G LRG_993p1:p.Pro252Arg P11362:p.Pro252Arg - Protein change
- P252R, P244R, P250R, P283R, P161R, P163R
- Other names
- -
- Canonical SPDI
- NC_000008.11:38424689:G:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| FGFR1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
992 | 1122 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 2, 2022 | RCV000017670.33 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 27, 2021 | RCV000017669.33 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2023 | RCV000644520.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 8, 2022 | RCV001200303.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 17, 2021 | RCV002496391.3 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 27, 2021)
|
criteria provided, single submitter
Method: research
|
Pfeiffer syndrome
Affected status: yes
Allele origin:
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV002012499.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
ACMG codes: PS3; PS4; PM2; PP1; PP3; PP5
Number of individuals with the variant: 1
Clinical Features:
Fetal growth restriction (present) , Small for gestational age (present) , Birth length less than 3rd percentile (present) , Micrognathia (present) , Abnormality of the … (more)
Fetal growth restriction (present) , Small for gestational age (present) , Birth length less than 3rd percentile (present) , Micrognathia (present) , Abnormality of the face (present) , Stridor (present) , Epicanthus (present) , Low-set, posteriorly rotated ears (present) , Protruding ear (present) , Anteverted nares (present) , Depressed nasal bridge (present) , Hypoplasia of the maxilla (present) , Micrognathia (present) , Retrognathia (present) , 2-3 toe syndactyly (present) , Shallow orbits (present) , Malar flattening (present) (less)
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Pathogenic
(Jul 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Pfeiffer syndrome
Jackson-Weiss syndrome Hypogonadotropic hypogonadism 2 with or without anosmia Osteoglophonic dysplasia Trigonocephaly 1 Encephalocraniocutaneous lipomatosis Hartsfield-Bixler-Demyer syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002812328.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002319172.2
First in ClinVar: Apr 02, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a … (more)
Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a damaging effect potentially via aberrant activation of downstream target Cbfa1 (Ibrahimi et al., 2004; Zhou et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23329143, 27065010, 7795583, 24127277, 10861678, 14564217, 7874169, 16957473, 24497711, 10942429, 31837199, 31016899, 32510873, 31167513, 32139749, 30207415, 34159400, 31785789, 14613973, 25251565) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Pfeiffer syndrome
Affected status: yes
Allele origin:
germline
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004030499.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pfeiffer syndrome
Hypogonadotropic hypogonadism 2 with or without anosmia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000766219.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). This variant is present in population databases (rs121909627, gnomAD 0.0009%). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16279). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973). (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Jackson-Weiss syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768161.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 [HH2] (MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with FGFR1-related conditions. It has mainly been reported in individuals with Pfeiffer syndrome (MIM#101600) but has been observed in one individual with Jackson-Weiss syndrome (MIM#123150) (ClinVar, LOVD, DECIPHER, PMIDs: 24127277, 31837199, 1456217, 10861678). (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)
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Pathogenic
(Jun 01, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371225.24
First in ClinVar: Jul 16, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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JACKSON-WEISS SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037947.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 14, 2019 |
Comment on evidence:
Pfeiffer Syndrome By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (101600), Muenke et al. (1994) found a C-to-G transversion at position 755 of … (more)
Pfeiffer Syndrome By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (101600), Muenke et al. (1994) found a C-to-G transversion at position 755 of exon 5, predicting a pro252-to-arg substitution located between the second and third putative Ig domain of the FGFR1 protein. Proline residue is highly conserved in evolution, being present in chicken, mouse, rat, and all 4 human FGFR genes. Jackson-Weiss Syndrome Roscioli et al. (2000) reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome (JWS; 123150) who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation in the FGFR1 gene. Variant Function By surface plasmon resonance analysis and X-ray crystallography, Ibrahimi et al. (2004) characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R mutation and the FGFR3c P250R (134934.0014) mutation exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (600921) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of the P252R mutant in complex with FGF2 showed that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to the gain-of-function interactions that occur in the crystal structure of the FGFR2c P253R (176943.0011) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P252R mutant nor the FRGR3c P250R mutant bound appreciably to FGF7 (148180) or FGF10 (602115). Ibrahimi et al. (2004) suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome (101600) and Muenke syndrome (602849) are less severe than limb abnormalities observed in Apert syndrome (101200). (less)
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Pathogenic
(Jan 01, 2004)
|
no assertion criteria provided
Method: literature only
|
PFEIFFER SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037946.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 14, 2019 |
Comment on evidence:
Pfeiffer Syndrome By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (101600), Muenke et al. (1994) found a C-to-G transversion at position 755 of … (more)
Pfeiffer Syndrome By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (101600), Muenke et al. (1994) found a C-to-G transversion at position 755 of exon 5, predicting a pro252-to-arg substitution located between the second and third putative Ig domain of the FGFR1 protein. Proline residue is highly conserved in evolution, being present in chicken, mouse, rat, and all 4 human FGFR genes. Jackson-Weiss Syndrome Roscioli et al. (2000) reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome (JWS; 123150) who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation in the FGFR1 gene. Variant Function By surface plasmon resonance analysis and X-ray crystallography, Ibrahimi et al. (2004) characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R mutation and the FGFR3c P250R (134934.0014) mutation exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (600921) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of the P252R mutant in complex with FGF2 showed that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to the gain-of-function interactions that occur in the crystal structure of the FGFR2c P253R (176943.0011) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P252R mutant nor the FRGR3c P250R mutant bound appreciably to FGF7 (148180) or FGF10 (602115). Ibrahimi et al. (2004) suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome (101600) and Muenke syndrome (602849) are less severe than limb abnormalities observed in Apert syndrome (101200). (less)
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Pathogenic
(Jun 17, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Pfeiffer syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011764.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a damaging effect potentially via aberrant activation of downstream target Cbfa1 (Ibrahimi et al., 2004; Zhou et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23329143, 27065010, 7795583, 24127277, 10861678, 14564217, 7874169, 16957473, 24497711, 10942429, 31837199, 31016899, 32510873, 31167513, 32139749, 30207415, 34159400, 31785789, 14613973, 25251565)
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). This variant is present in population databases (rs121909627, gnomAD 0.0009%). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16279). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 [HH2] (MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with FGFR1-related conditions. It has mainly been reported in individuals with Pfeiffer syndrome (MIM#101600) but has been observed in one individual with Jackson-Weiss syndrome (MIM#123150) (ClinVar, LOVD, DECIPHER, PMIDs: 24127277, 31837199, 1456217, 10861678). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
ACMG codes: PS3; PS4; PM2; PP1; PP3; PP5
Comment:
Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a damaging effect potentially via aberrant activation of downstream target Cbfa1 (Ibrahimi et al., 2004; Zhou et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23329143, 27065010, 7795583, 24127277, 10861678, 14564217, 7874169, 16957473, 24497711, 10942429, 31837199, 31016899, 32510873, 31167513, 32139749, 30207415, 34159400, 31785789, 14613973, 25251565)
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). This variant is present in population databases (rs121909627, gnomAD 0.0009%). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16279). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 [HH2] (MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with FGFR1-related conditions. It has mainly been reported in individuals with Pfeiffer syndrome (MIM#101600) but has been observed in one individual with Jackson-Weiss syndrome (MIM#123150) (ClinVar, LOVD, DECIPHER, PMIDs: 24127277, 31837199, 1456217, 10861678). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NGS targeted screening of 100 Scandinavian patients with coronal synostosis. | Topa A | American journal of medical genetics. Part A | 2020 | PMID: 31837199 |
| Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. | Bennett JT | American journal of human genetics | 2016 | PMID: 26942290 |
| Variable expressivity of pfeiffer syndrome in a family with FGFR1 p.Pro252Arg mutation. | Bessenyei B | American journal of medical genetics. Part A | 2014 | PMID: 25251565 |
| Mutational identification of fibroblast growth factor receptor 1 and fibroblast growth factor receptor 2 genes in craniosynostosis in Indian population. | Pandey RK | Indian journal of human genetics | 2013 | PMID: 24497711 |
| Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients. | Roscioli T | American journal of medical genetics. Part C, Seminars in medical genetics | 2013 | PMID: 24127277 |
| FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. | Simonis N | Journal of medical genetics | 2013 | PMID: 23812909 |
| Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. | Kim SH | Journal of neuroendocrinology | 2008 | PMID: 18034870 |
| FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report. | Hackett A | Clinical dysmorphology | 2006 | PMID: 16957473 |
| Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. | Ibrahimi OA | Human molecular genetics | 2004 | PMID: 14613973 |
| The appearance of the feet in Pfeiffer syndrome caused by FGFR1 P252R mutation. | Rossi M | Clinical dysmorphology | 2003 | PMID: 14564217 |
| A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. | Zhou YX | Human molecular genetics | 2000 | PMID: 10942429 |
| Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature. | Roscioli T | American journal of medical genetics | 2000 | PMID: 10861678 |
| Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. | Schell U | Human molecular genetics | 1995 | PMID: 7795583 |
| A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. | Muenke M | Nature genetics | 1994 | PMID: 7874169 |
| An evaluation of the nasolabial angle and the relative inclinations of the nose and upper lip. | Fitzgerald JP | American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics | 1992 | PMID: 1456217 |
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Text-mined citations for rs121909627 ...
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Record last updated Oct 20, 2024
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