NM_000141.5(FGFR2):c.1021A>C (p.Thr341Pro) AND Pfeiffer syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 17, 2016
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:: RCV000014194.30

Allele description [Variation Report for NM_000141.5(FGFR2):c.1021A>C (p.Thr341Pro)]

NM_000141.5(FGFR2):c.1021A>C (p.Thr341Pro)

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.1021A>C (p.Thr341Pro)

HGVS:

NC_000010.11:g.121517382T>G
NG_012449.2:g.86077A>C
NM_000141.5:c.1021A>CMANE SELECT
NM_001144913.1:c.1087+1300A>C
NM_001144914.1:c.749-2063A>C
NM_001144915.2:c.754A>C
NM_001144916.2:c.676A>C
NM_001144917.2:c.939+2597A>C
NM_001144918.2:c.676A>C
NM_001144919.2:c.820+1300A>C
NM_001320654.2:c.337A>C
NM_001320658.2:c.1021A>C
NM_022970.4:c.1087+1300A>C
NM_023029.2:c.754A>C
NP_000132.3:p.Thr341Pro
NP_000132.3:p.Thr341Pro
NP_001138387.1:p.Thr252Pro
NP_001138388.1:p.Thr226Pro
NP_001138390.1:p.Thr226Pro
NP_001307583.1:p.Thr113Pro
NP_001307587.1:p.Thr341Pro
NP_075418.1:p.Thr252Pro
LRG_994t1:c.1021A>C
LRG_994:g.86077A>C
LRG_994p1:p.Thr341Pro
NC_000010.10:g.123276896T>G
NM_000141.4:c.1021A>C
NR_073009.2:n.1457A>C
P21802:p.Thr341Pro
p.[Thr341Pro]

Protein change:

T113P; THR341PRO

Links:

UniProtKB: P21802#VAR_004135; OMIM: 176943.0012; dbSNP: rs121918495

NCBI 1000 Genomes Browser:

rs121918495

Molecular consequence:

NM_001144913.1:c.1087+1300A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001144914.1:c.749-2063A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001144917.2:c.939+2597A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001144919.2:c.820+1300A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_022970.4:c.1087+1300A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000141.5:c.1021A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001144915.2:c.754A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001144916.2:c.676A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001144918.2:c.676A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001320654.2:c.337A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001320658.2:c.1021A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_023029.2:c.754A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_073009.2:n.1457A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Pfeiffer syndrome (ACS5)
Synonyms:: ACS V; Pfeiffer type acrocephalosyndactyly; Acrocephalosyndactyly, type 5
Identifiers:: MONDO: MONDO:0007043; MedGen: C0220658; Orphanet: 710; OMIM: 101600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034442	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 1995)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000328389	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,
SCV004048554	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034442

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 1995)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000328389

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,

SCV004048554

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000034442.1

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

Description

In a sporadic case of Pfeiffer syndrome (101600), Rutland et al. (1995) observed an A-to-C transversion at nucleotide 1033 changing thr to pro at position 341, adjacent to the cys342 residue that has been found altered in cases of Crouzon syndrome and Pfeiffer syndrome (e.g., 176943.0001).

#	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, SCV000328389.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048554.1

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

Description

The missense variant c.1021A>C(p.Thr341Pro) in the FGFR2 gene has been reported in heterozygous state in individuals affected with Pfeiffer syndrome (Lajeunie E. et al., 2006). Experimental studies have shown that this variant is an activating variant which induced receptor dimerization and elevated levels of tyrosine kinase activity (Robertson SC. et al.,1998). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Threonine at position 341 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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