ClinVar Genomic variation as it relates to human health
NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)
Variation ID: 13263 Accession: VCV000013263.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.13 10: 121517378 (GRCh38) [ NCBI UCSC ] 10: 123276892 (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 Apr 4, 2013 Jul 15, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000141.5:c.1025G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000132.3:p.Cys342Tyr missense NM_022970.4:c.1087+1304G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001144913.1:c.1087+1304G>A intron variant NM_001144914.1:c.749-2059G>A intron variant NM_001144915.2:c.758G>A NP_001138387.1:p.Cys253Tyr missense NM_001144916.2:c.680G>A NP_001138388.1:p.Cys227Tyr missense NM_001144917.2:c.939+2601G>A intron variant NM_001144918.2:c.680G>A NP_001138390.1:p.Cys227Tyr missense NM_001144919.2:c.820+1304G>A intron variant NM_001320654.2:c.341G>A NP_001307583.1:p.Cys114Tyr missense NM_001320658.2:c.1025G>A NP_001307587.1:p.Cys342Tyr missense NM_023029.2:c.758G>A NP_075418.1:p.Cys253Tyr missense NR_073009.2:n.1461G>A non-coding transcript variant NC_000010.11:g.121517378C>T NC_000010.10:g.123276892C>T NG_012449.2:g.86081G>A LRG_994:g.86081G>A LRG_994t1:c.1025G>A LRG_994p1:p.Cys342Tyr P21802:p.Cys342Tyr - Protein change
- C342Y, C253Y, C227Y, C114Y
- Other names
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- Canonical SPDI
- NC_000010.11:121517377:C:T
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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.
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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
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. |
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FGFR2 | - | - |
GRCh38 GRCh37 |
738 | 792 |
Conditions - Germline
Condition
Help
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
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. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 30, 2020 | RCV000014173.27 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 1995 | RCV000014174.27 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000547490.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762801.4 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2021 | RCV001090933.26 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 31, 2019 | RCV001196204.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2021 | RCV001730471.4 |
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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Pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848390.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Cys342Tyr variant in FGFR2 has been reported in the literature in >20 individuals with syndromic craniosynostosis (such as Crouzon or Pfeiffer syndromes) and segregated … (more)
The p.Cys342Tyr variant in FGFR2 has been reported in the literature in >20 individuals with syndromic craniosynostosis (such as Crouzon or Pfeiffer syndromes) and segregated with disease in four affected individuals from one family (Reardon 2013 PMID: 7987400; Schwartz 1996 PMID: 8650126; Roscioli 2013 PMID: 24127277; Paumard-Hernández 2015 PMID: 25271085). This variant was also confirmed de novo in a boy with a clinical diagnosis of Crouzon syndrome through trio WGS analysis by the Broad Institute Rare Genomes Project. This variant has been reported in ClinVar as pathogenic by multiple labs (Variation ID 13263). It is absent from large population studies. In vitro functional studies support an impact on protein function (Krejci 2012 PMID: 22558232), and animal models in mice have shown that this variant in heterozygous mice causes features of syndromic craniosynostosis (Eswarakumar 2004 PMID: 15316116). Additionally, other missense variants in this codon (p.Cys342Arg, p.Cys342Trp, p.Cys342Ser, p.Cys342Phe, p.Cys342Gly) have been identified in individuals with Crouzon syndrome suggesting that this position is critical for protein function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant craniosynostosis. ACMG/AMP Criteria applied: PS2, PS3, PS4, PM1, PM2, PP1. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893151.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Feb 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
Affected status: yes
Allele origin:
germline
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Department of Medical Genetics, Oslo University Hospital
Accession: SCV001437555.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Craniosynostosis (present)
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Likely pathogenic
(May 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366745.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3,PP4.
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Pathogenic
(Sep 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Craniosynostosis syndrome
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV001980674.1
First in ClinVar: Oct 25, 2021 Last updated: Oct 25, 2021 |
Comment:
The c.1025G>A;p.(Cys342Tyr) variant has been published as a pathogenic variant in individuals affected with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 24127277, 25271085; … (more)
The c.1025G>A;p.(Cys342Tyr) variant has been published as a pathogenic variant in individuals affected with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 24127277, 25271085; GeneOne, DASA) - PS4; ClinVar contains an entry for this variant (Variation ID: 13263); Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22558232, 8755573, 20133659, 15316116) - PS3; This variant is not present in population databases (rs121918487 - gnomAD no frequency; ABraOM no frequency - abraom.ib.usp.br) - PM2; Pathogenic missense variants in this residue (ClinVar ID: 374820 - c.1025G>C;p.(Cys342Ser); ClinVar ID: 374819 - c.1025G>T;p.(Cys342Phe)) - PM5; It has also been shown to segregate with Crouzon syndrome in a family (PMID: 8650126) - PP1; 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; In silico analysis predicts this variant is probably damaging to the protein structure/function - 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
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Pathogenic
(Sep 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000328393.2
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023
Comment:
Clinical Testing
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Number of individuals with the variant: 15
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Pathogenic
(Dec 15, 2021)
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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: SCV001784745.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that this variant results in aberrant cell growth and blocks cellular differentiation (Mansukhani et al., 2000), while experimental mice models demonstrate … (more)
Published functional studies demonstrate that this variant results in aberrant cell growth and blocks cellular differentiation (Mansukhani et al., 2000), while experimental mice models demonstrate that p.(C342Y) leads to significant defects in skull development (Holmes et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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: 25692891, 20133659, 8650126, 25271085, 7719345, 9677057, 23754559, 24127277, 7987400, 27228464, 8644708, 11781872, 22558232, 15316116, 8755573, 7607643, 28901406, 26362256, 10851026, 31837199, 30048539) (less)
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: research
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FGFR2-related craniosynostosis
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123095.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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Pathogenic
(Nov 30, 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: SCV000659603.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 342 of the FGFR2 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 342 of the FGFR2 protein (p.Cys342Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 8650126, 24127277, 25271085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13263). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 8755573, 15316116, 20133659, 22558232). This variant disrupts the p.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277, 25271085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2017)
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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: SCV001246716.23
First in ClinVar: May 12, 2020 Last updated: Jul 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 01, 1995)
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no assertion criteria provided
Method: literature only
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CROUZON SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034421.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 unrelated individuals with Crouzon syndrome (123500), Reardon et al. (1994) found a G-to-A transition at nucleotide 1037 in the B exon of the … (more)
In 3 unrelated individuals with Crouzon syndrome (123500), Reardon et al. (1994) found a G-to-A transition at nucleotide 1037 in the B exon of the FGFR2 gene. This was predicted to result in a cys342-to-tyr (C342Y) substitution within the third Ig domain. The same mutation was found by Rutland et al. (1995) in a patient with Pfeiffer syndrome (101600), not Crouzon syndrome. Steinberger et al. (1995) found mutations at codon 342 in 3 sporadic cases of Crouzon syndrome. Two of them were G-to-A transitions at position 1037, the mutation described by Reardon et al. (1994). The third was a C-to-G transversion at position 1038, resulting in replacement of cysteine by tryptophan (176943.0013). Steinberger et al. (1995) pointed out that a mutation in codon 342 had been found in 8 out of 17 cases of Crouzon syndrome and that in 9 cases the mutation occurred at 5 other positions, suggesting that codon 342 of exon B of the FGFR2 gene may be disposed to mutations in Crouzon syndrome. The substitutions of cysteine that appeared to be leading causes of Crouzon syndrome occur in the immunoglobulin-like domain of FGFR2. (less)
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Pathogenic
(Jul 01, 1995)
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no assertion criteria provided
Method: literature only
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PFEIFFER SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034422.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 unrelated individuals with Crouzon syndrome (123500), Reardon et al. (1994) found a G-to-A transition at nucleotide 1037 in the B exon of the … (more)
In 3 unrelated individuals with Crouzon syndrome (123500), Reardon et al. (1994) found a G-to-A transition at nucleotide 1037 in the B exon of the FGFR2 gene. This was predicted to result in a cys342-to-tyr (C342Y) substitution within the third Ig domain. The same mutation was found by Rutland et al. (1995) in a patient with Pfeiffer syndrome (101600), not Crouzon syndrome. Steinberger et al. (1995) found mutations at codon 342 in 3 sporadic cases of Crouzon syndrome. Two of them were G-to-A transitions at position 1037, the mutation described by Reardon et al. (1994). The third was a C-to-G transversion at position 1038, resulting in replacement of cysteine by tryptophan (176943.0013). Steinberger et al. (1995) pointed out that a mutation in codon 342 had been found in 8 out of 17 cases of Crouzon syndrome and that in 9 cases the mutation occurred at 5 other positions, suggesting that codon 342 of exon B of the FGFR2 gene may be disposed to mutations in Crouzon syndrome. The substitutions of cysteine that appeared to be leading causes of Crouzon syndrome occur in the immunoglobulin-like domain of FGFR2. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929001.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Crouzon syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510536.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001956788.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001974160.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants. | Paumard-Hernández B | European journal of human genetics : EJHG | 2015 | PMID: 25271085 |
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 |
Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. | Krejci P | PloS one | 2012 | PMID: 22558232 |
Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate. | Snyder-Warwick AK | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20133659 |
A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. | Eswarakumar VP | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15316116 |
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 |
Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras. | Galvin BD | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8755573 |
First-trimester prenatal diagnosis of Crouzon syndrome. | Schwartz M | Prenatal diagnosis | 1996 | PMID: 8650126 |
Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. | Rutland P | Nature genetics | 1995 | PMID: 7719345 |
Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome. | Steinberger D | Human genetics | 1995 | PMID: 7607643 |
Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. | Reardon W | Nature genetics | 1994 | PMID: 7987400 |
http://docm.genome.wustl.edu/variants/ENST00000351936:c.1025G>A | - | - | - | - |
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Text-mined citations for rs121918487 ...
HelpRecord last updated Jul 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.