NM_000141.5(FGFR2):c.1024T>A (p.Cys342Ser) AND FGFR2-related craniosynostosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV000655416.9

Allele description [Variation Report for NM_000141.5(FGFR2):c.1024T>A (p.Cys342Ser)]

NM_000141.5(FGFR2):c.1024T>A (p.Cys342Ser)

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.1024T>A (p.Cys342Ser)

HGVS:

NC_000010.11:g.121517379A>T
NG_012449.2:g.86080T>A
NM_000141.5:c.1024T>AMANE SELECT
NM_001144913.1:c.1087+1303T>A
NM_001144914.1:c.749-2060T>A
NM_001144915.2:c.757T>A
NM_001144916.2:c.679T>A
NM_001144917.2:c.939+2600T>A
NM_001144918.2:c.679T>A
NM_001144919.2:c.820+1303T>A
NM_001320654.2:c.340T>A
NM_001320658.2:c.1024T>A
NM_022970.4:c.1087+1303T>A
NM_023029.2:c.757T>A
NP_000132.3:p.Cys342Ser
NP_000132.3:p.Cys342Ser
NP_001138387.1:p.Cys253Ser
NP_001138388.1:p.Cys227Ser
NP_001138390.1:p.Cys227Ser
NP_001307583.1:p.Cys114Ser
NP_001307587.1:p.Cys342Ser
NP_075418.1:p.Cys253Ser
LRG_994t1:c.1024T>A
LRG_994:g.86080T>A
LRG_994p1:p.Cys342Ser
NC_000010.10:g.123276893A>T
NM_000141.4:c.1024T>A
NR_073009.2:n.1460T>A
P21802:p.Cys342Ser
p.[Cys342Ser]

Protein change:

C114S; CYS342SER

Links:

UniProtKB: P21802#VAR_004138; OMIM: 176943.0003; dbSNP: rs121918488

NCBI 1000 Genomes Browser:

rs121918488

Molecular consequence:

NM_001144913.1:c.1087+1303T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2060T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2600T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1303T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1303T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.1024T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.757T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.679T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.679T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.340T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.1024T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.757T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1460T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000777346	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7987400, 8644708, 9586546, 10541159, 12884424, 12884434, 25271085, 26362256, 24127277, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777346

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (10)
[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

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, Day D, Goldberg R, Daentl DL, Przylepa KA, Abrams LJ, Graham JM Jr, Feingold M, Moeschler JB, Rawnsley E, Scott AF, Jabs EW.

Am J Hum Genet. 1996 Mar;58(3):491-8.

PubMed [citation]

PMID:: 8644708
PMCID:: PMC1914562

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000777346.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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 individual(s) with syndromic craniosynostosis, including Pfeiffer and Crouzen syndromes (PMID: 7987400, 8644708, 9586546, 10541159, 12884424, 12884434, 24127277, 25271085, 26362256). ClinVar contains an entry for this variant (Variation ID: 13267). 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%. 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.

#	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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