NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu) AND FGFR2-related craniosynostosis

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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 28, 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:: RCV001313539.4

Allele description

NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu)

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.755C>T (p.Ser252Leu)

Other names:

NM_000141.4:c.755C>T(p.Ser252Leu); NM_001144913.1:c.755C>T(p.Ser252Leu); NM_001144915.1:c.488C>T(p.Ser163Leu); NM_001144916.1:c.410C>T(p.Ser137Leu); NM_001144917.1:c.755C>T(p.Ser252Leu); NM_001144918.1:c.410C>T(p.Ser137Leu); NM_001144919.1:c.488C>T(p.Ser163Leu); NM_022970.3:c.755C>T(p.Ser252Leu); NM_023029.2:c.488C>T(p.Ser163Leu)

HGVS:

NC_000010.11:g.121520163G>A
NG_012449.2:g.83296C>T
NM_000141.5:c.755C>TMANE SELECT
NM_001144913.1:c.755C>T
NM_001144914.1:c.749-4844C>T
NM_001144915.2:c.488C>T
NM_001144916.2:c.410C>T
NM_001144917.2:c.755C>T
NM_001144918.2:c.410C>T
NM_001144919.2:c.488C>T
NM_001320654.2:c.71C>T
NM_001320658.2:c.755C>T
NM_022969.1:c.755C>T
NM_022970.4:c.755C>T
NM_023029.2:c.488C>T
NP_000132.3:p.Ser252Leu
NP_000132.3:p.Ser252Leu
NP_001138385.1:p.Ser252Leu
NP_001138387.1:p.Ser163Leu
NP_001138388.1:p.Ser137Leu
NP_001138389.1:p.Ser252Leu
NP_001138390.1:p.Ser137Leu
NP_001138391.1:p.Ser163Leu
NP_001307583.1:p.Ser24Leu
NP_001307587.1:p.Ser252Leu
NP_075258.1:p.Ser252Leu
NP_075259.4:p.Ser252Leu
NP_075259.4:p.Ser252Leu
NP_075418.1:p.Ser163Leu
LRG_994t1:c.755C>T
LRG_994t2:c.755C>T
LRG_994:g.83296C>T
LRG_994p1:p.Ser252Leu
LRG_994p2:p.Ser252Leu
NC_000010.10:g.123279677G>A
NM_000141.4:c.755C>T
NM_000141.5:c.755C>T
NM_022970.3:c.755C>T
NR_073009.2:n.1043C>T

Protein change:

S137L

Links:

dbSNP: rs79184941

NCBI 1000 Genomes Browser:

rs79184941

Molecular consequence:

NM_001144914.1:c.749-4844C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144913.1:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.488C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.410C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144917.2:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.410C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001144919.2:c.488C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.71C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022969.1:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022970.4:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.488C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1043C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

Recent activity

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Mus musculus intersectin 2 (Itsn2), transcript variant 1, mRNA
Mus musculus intersectin 2 (Itsn2), transcript variant 1, mRNA
gi|379642566|ref|NM_001198968.2|

Nucleotide
Mus musculus solute carrier family 22 (organic cation transporter), member 5 (Sl...
Mus musculus solute carrier family 22 (organic cation transporter), member 5 (Slc22a5), transcript variant 1, mRNA
gi|226958323|ref|NM_011396.3|

Nucleotide
Mus musculus 5'-3' exoribonuclease 1, mRNA (cDNA clone IMAGE:30013883), partial ...
Mus musculus 5'-3' exoribonuclease 1, mRNA (cDNA clone IMAGE:30013883), partial cds
gi|32484212|gb|BC054108.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001504038	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9002682, 11711827, 27683237, 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380, 9700203, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001504038

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 28, 2023)

germline

clinical testing

PubMed (13)
[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

Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.

Oldridge M, Lunt PW, Zackai EH, McDonald-McGinn DM, Muenke M, Moloney DM, Twigg SR, Heath JK, Howard TD, Hoganson G, Gagnon DM, Jabs EW, Wilkie AO.

Hum Mol Genet. 1997 Jan;6(1):137-43.

PubMed [citation]

PMID:: 9002682

Sequence analysis of fibroblast growth factor receptor 2 ( FGFR2 ) in Japanese patients with craniosynostosis.

Sakai N, Tokunaga K, Yamazaki Y, Shida H, Sakata Y, Susami T, Nakakita N, Takato T, Uchinuma E.

J Craniofac Surg. 2001 Nov;12(6):580-5.

PubMed [citation]

PMID:: 11711827

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV001504038.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is present in population databases (rs79184941, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 252 of the FGFR2 protein (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 549484). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser252 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FGFR2 function (PMID: 9700203). 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.

#	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 16, 2024

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