NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr) AND Crouzon syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Sep 30, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000014173.27

Allele description

NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)

Gene:

FGFR2:fibroblast growth factor receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q26.13

Genomic location:

Preferred name:

NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)

HGVS:

NC_000010.11:g.121517378C>T
NG_012449.2:g.86081G>A
NM_000141.5:c.1025G>AMANE SELECT
NM_001144913.1:c.1087+1304G>A
NM_001144914.1:c.749-2059G>A
NM_001144915.2:c.758G>A
NM_001144916.2:c.680G>A
NM_001144917.2:c.939+2601G>A
NM_001144918.2:c.680G>A
NM_001144919.2:c.820+1304G>A
NM_001320654.2:c.341G>A
NM_001320658.2:c.1025G>A
NM_022970.4:c.1087+1304G>A
NM_023029.2:c.758G>A
NP_000132.3:p.Cys342Tyr
NP_000132.3:p.Cys342Tyr
NP_001138387.1:p.Cys253Tyr
NP_001138388.1:p.Cys227Tyr
NP_001138390.1:p.Cys227Tyr
NP_001307583.1:p.Cys114Tyr
NP_001307587.1:p.Cys342Tyr
NP_075418.1:p.Cys253Tyr
LRG_994t1:c.1025G>A
LRG_994:g.86081G>A
LRG_994p1:p.Cys342Tyr
NC_000010.10:g.123276892C>T
NM_000141.4:c.1025G>A
NM_000141.5:c.1025G>A
NR_073009.2:n.1461G>A
P21802:p.Cys342Tyr
p.[Cys342Tyr]

Protein change:

C114Y; CYS342TYR

Links:

UniProtKB: P21802#VAR_004139; OMIM: 176943.0001; dbSNP: rs121918487

NCBI 1000 Genomes Browser:

rs121918487

Molecular consequence:

NM_001144913.1:c.1087+1304G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2059G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2601G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1304G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1304G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.1025G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.758G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.341G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.1025G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.758G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1461G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Crouzon syndrome
Synonyms:: CRANIOFACIAL DYSOSTOSIS, TYPE I; Crouzon craniofacial dysostosis; Crouzon disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007405; MeSH: D003394; MedGen: C0010273; Orphanet: 207; OMIM: 123500; Human Phenotype Ontology: HP:0004439

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034421	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1995)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 7719345, 7607643, 7987400
SCV000328393	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Sep 17, 2016)	germline	clinical testing	Citation Link,
SCV000510536	Database of Curated Mutations (DoCM)	no assertion criteria provided	Likely pathogenic (May 13, 2016)	somatic	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001437555	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848390	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 30, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24127277, 22558232, 25271085, 7987400, 15316116, 8650126, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	16	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.

Rutland P, Pulleyn LJ, Reardon W, Baraitser M, Hayward R, Jones B, Malcolm S, Winter RM, Oldridge M, Slaney SF, et al.

Nat Genet. 1995 Feb;9(2):173-6.

PubMed [citation]

PMID:: 7719345

Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome.

Steinberger D, Mulliken JB, Müller U.

Hum Genet. 1995 Jul;96(1):113-5.

PubMed [citation]

PMID:: 7607643

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000034421.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000328393.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		15	not provided	not provided	not provided

From Database of Curated Mutations (DoCM), SCV000510536.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Medical Genetics, Oslo University Hospital, SCV001437555.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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