ClinVar Genomic variation as it relates to human health
NM_000141.5(FGFR2):c.1025G>C (p.Cys342Ser)
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>C (p.Cys342Ser)
Variation ID: 374820 Accession: VCV000374820.21
- 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 Jan 20, 2017 Apr 15, 2024 Sep 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000141.5:c.1025G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000132.3:p.Cys342Ser missense NM_022970.4:c.1087+1304G>C 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>C intron variant NM_001144914.1:c.749-2059G>C intron variant NM_001144915.2:c.758G>C NP_001138387.1:p.Cys253Ser missense NM_001144916.2:c.680G>C NP_001138388.1:p.Cys227Ser missense NM_001144917.2:c.939+2601G>C intron variant NM_001144918.2:c.680G>C NP_001138390.1:p.Cys227Ser missense NM_001144919.2:c.820+1304G>C intron variant NM_001320654.2:c.341G>C NP_001307583.1:p.Cys114Ser missense NM_001320658.2:c.1025G>C NP_001307587.1:p.Cys342Ser missense NM_023029.2:c.758G>C NP_075418.1:p.Cys253Ser missense NR_073009.2:n.1461G>C non-coding transcript variant NC_000010.11:g.121517378C>G NC_000010.10:g.123276892C>G NG_012449.2:g.86081G>C LRG_994:g.86081G>C LRG_994t1:c.1025G>C LRG_994p1:p.Cys342Ser - Protein change
- C342S, C227S, C253S, C114S
- Other names
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- Canonical SPDI
- NC_000010.11:121517377:C:G
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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
Help
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
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
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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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Pathogenic (1) |
criteria provided, single submitter
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Sep 17, 2016 | RCV000415499.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV000560038.8 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV000856727.4 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 17, 2023 | RCV001729573.12 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 13, 2023 | RCV003155177.5 |
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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Crouzon syndrome
Affected status: yes
Allele origin:
unknown
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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999272.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Hypertelorism (present) , Depressed nasal tip (present) , Flat occiput (present) , Facial asymmetry (present) , Downslanted palpebral fissures (present) , Craniosynostosis (present) , Choanal … (more)
Hypertelorism (present) , Depressed nasal tip (present) , Flat occiput (present) , Facial asymmetry (present) , Downslanted palpebral fissures (present) , Craniosynostosis (present) , Choanal stenosis (present) , Broad hallux (present) , Broad thumb (present) , Brachyturricephaly (present) , Micrognathia (present) , Short upper lip (present) , Proptosis (present) (less)
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Pathogenic
(Sep 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Jackson-Weiss syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000328395.2
First in ClinVar: Jan 20, 2017 Last updated: Mar 04, 2023 |
Number of individuals with the variant: 4
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Pathogenic
(Sep 17, 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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GeneDx
Accession: SCV002004274.3
First in ClinVar: Nov 06, 2021 Last updated: Sep 22, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at 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: 23754559, 26362256, 24127277, 9586546, 12884424, 8644708, 9385368, 16418739, 34133757, 36316869, 26582918) (less)
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Pathogenic
(Apr 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pfeiffer syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175398.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The FGFR2 c.1025G>C variant is classified as Pathogenic (PS4, PS3_Moderate, PM1, PM2, PP4) The FGFR2 c.1025G>C variant is a single nucleotide change in exon 8/18 … (more)
The FGFR2 c.1025G>C variant is classified as Pathogenic (PS4, PS3_Moderate, PM1, PM2, PP4) The FGFR2 c.1025G>C variant is a single nucleotide change in exon 8/18 of the FGFR2 gene, which is predicted to change the amino acid cysteine at position 342 in the protein, to serine. This variant has been reported in at least 15 probands with a clinical presentation of Craniosynostosis/Pfeiffer syndrome (PMID# 9586546, 12884424, 24127277, 26362256, 9385368) (PS4) and is located in the conserved Cys342 amino acid where multiple changes to the same amino acid (p.C342R/G/F/W/Y) is reported in individuals with craniosynostosis (PM1). Well-established functional studies show a deleterious effect as a result of change to this conserved amino acid. A mouse model of the most common change to this amino acid (p.C342Y) reflected a craniosysnostosis phenotype. Biochemically these substitutions are considered 'functionally identical' (PMID#26362256) (PS3_moderate). The clinical features of this case are highly specific for FGFR2 and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). This variant is absent from population databases (PM2), has been reported in dbSNP (rs121918487), is reported HGMD as disease causing (CM960647) and is reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 374820). literature: PubMed: 8644708 (less)
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Pathogenic
(Aug 10, 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: SCV000659604.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, 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 serine, which is neutral and polar, at codon 342 of the FGFR2 protein (p.Cys342Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with craniosynostosis syndromes including Pfeiffer or Crouzen syndromes (PMID: 8644708, 9586546, 12884424, 12884434, 24127277, 25271085, 26362256). ClinVar contains an entry for this variant (Variation ID: 374820). 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. 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). 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
(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: SCV003916648.7
First in ClinVar: Apr 23, 2023 Last updated: Apr 15, 2024 |
Comment:
FGFR2: PM1:Strong, PM2, PS2:Moderate, PS4:Moderate, PP3
Number of individuals with the variant: 1
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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: SCV001979677.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 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: SCV001980302.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Apr 15, 2022)
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no assertion criteria provided
Method: research
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Pfeiffer syndrome
Affected status: yes
Allele origin:
germline
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Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University
Accession: SCV003844079.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Clinical Features:
Ventriculomegaly (present)
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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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FGFR2 mutation in 46,XY sex reversal with craniosynostosis. | Bagheri-Fam S | Human molecular genetics | 2015 | PMID: 26362256 |
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 |
Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10]. | Sauter S | American journal of medical genetics. Part A | 2003 | PMID: 12884434 |
Screening of patients with craniosynostosis: molecular strategy. | Chun K | American journal of medical genetics. Part A | 2003 | PMID: 12884424 |
Mutations in fibroblast growth factor receptor 2 gene and craniosynostotic syndromes in Japanese children. | Nagase T | The Journal of craniofacial surgery | 1998 | PMID: 9586546 |
Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders. | Tartaglia M | Human genetics | 1997 | PMID: 9385368 |
FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. | Meyers GA | American journal of human genetics | 1996 | PMID: 8644708 |
Text-mined citations for rs121918487 ...
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.