NM_000141.5(FGFR2):c.1019A>G (p.Tyr340Cys) AND FGFR2-related craniosynostosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 24, 2021
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:: RCV001232531.5

Allele description [Variation Report for NM_000141.5(FGFR2):c.1019A>G (p.Tyr340Cys)]

NM_000141.5(FGFR2):c.1019A>G (p.Tyr340Cys)

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.1019A>G (p.Tyr340Cys)

HGVS:

NC_000010.11:g.121517384T>C
NG_012449.2:g.86075A>G
NM_000141.5:c.1019A>GMANE SELECT
NM_001144913.1:c.1087+1298A>G
NM_001144914.1:c.749-2065A>G
NM_001144915.2:c.752A>G
NM_001144916.2:c.674A>G
NM_001144917.2:c.939+2595A>G
NM_001144918.2:c.674A>G
NM_001144919.2:c.820+1298A>G
NM_001320654.2:c.335A>G
NM_001320658.2:c.1019A>G
NM_022970.4:c.1087+1298A>G
NM_023029.2:c.752A>G
NP_000132.3:p.Tyr340Cys
NP_000132.3:p.Tyr340Cys
NP_001138387.1:p.Tyr251Cys
NP_001138388.1:p.Tyr225Cys
NP_001138390.1:p.Tyr225Cys
NP_001307583.1:p.Tyr112Cys
NP_001307587.1:p.Tyr340Cys
NP_075418.1:p.Tyr251Cys
LRG_994t1:c.1019A>G
LRG_994:g.86075A>G
LRG_994p1:p.Tyr340Cys
NC_000010.10:g.123276898T>C
NM_000141.4:c.1019A>G
NR_073009.2:n.1455A>G

Protein change:

Y112C

Links:

dbSNP: rs1554928884

NCBI 1000 Genomes Browser:

rs1554928884

Molecular consequence:

NM_001144913.1:c.1087+1298A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2065A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2595A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1298A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1298A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.1019A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.752A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.335A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.1019A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.752A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1455A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Mus musculus SPARC-like 1 (Sparcl1), transcript variant 3, mRNA
Mus musculus SPARC-like 1 (Sparcl1), transcript variant 3, mRNA
gi|227330560|ref|NM_010097.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001405093	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7987400, 8755573, 9521581, 16418739, 10394936, 27683237, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001405093

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2021)

germline

clinical testing

PubMed (7)
[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

Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.

Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S.

Nat Genet. 1994 Sep;8(1):98-103.

PubMed [citation]

PMID:: 7987400

Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras.

Galvin BD, Hart KC, Meyer AN, Webster MK, Donoghue DJ.

Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7894-9.

PubMed [citation]

PMID:: 8755573
PMCID:: PMC38845

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001405093.4

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr340 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7987400, 8755573, 9521581, 16418739). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 449398). This missense change has been observed in individual(s) with Pfeiffer syndrome (PMID: 10394936, 27683237). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 340 of the FGFR2 protein (p.Tyr340Cys).

#	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: Sep 29, 2024

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