NM_000141.5(FGFR2):c.940-2A>G AND FGFR2-related craniosynostosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 11, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000558628.9

Allele description [Variation Report for NM_000141.5(FGFR2):c.940-2A>G]

NM_000141.5(FGFR2):c.940-2A>G

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.940-2A>G

HGVS:

NC_000010.11:g.121517465T>C
NG_012449.2:g.85994A>G
NM_000141.5:c.940-2A>GMANE SELECT
NM_001144913.1:c.1087+1217A>G
NM_001144914.1:c.749-2146A>G
NM_001144915.2:c.673-2A>G
NM_001144916.2:c.595-2A>G
NM_001144917.2:c.939+2514A>G
NM_001144918.2:c.595-2A>G
NM_001144919.2:c.820+1217A>G
NM_001320654.2:c.256-2A>G
NM_001320658.2:c.940-2A>G
NM_022970.4:c.1087+1217A>G
NM_023029.2:c.673-2A>G
LRG_994t1:c.940-2A>G
LRG_994:g.85994A>G
NC_000010.10:g.123276979T>C
NM_000141.4:c.940-2A>G

Links:

dbSNP: rs1057519041

NCBI 1000 Genomes Browser:

rs1057519041

Molecular consequence:

NM_001144913.1:c.1087+1217A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2146A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2514A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1217A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1217A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.940-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001144915.2:c.673-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001144916.2:c.595-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001144918.2:c.595-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001320654.2:c.256-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001320658.2:c.940-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_023029.2:c.673-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: FGFR2-related craniosynostosis
Identifiers:: MedGen: CN231480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000659624	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 7795583, 16418739, 25271085, 270283566, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659624

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome.

Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, Viskochil DH, Stewart JM, Wolff G, Ohashi H, et al.

Hum Mol Genet. 1995 Mar;4(3):323-8.

PubMed [citation]

PMID:: 7795583

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659624.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects an acceptor splice site in intron 7 of the FGFR2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in FGFR2 cause disease. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 16418739, 25271085, 270283566). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374814). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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: Jun 8, 2025

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Relating variation to medicine