NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 1, 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:: RCV000644520.10

Allele description [Variation Report for NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)]

NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)

Gene:

FGFR1:fibroblast growth factor receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p11.23

Genomic location:

Preferred name:

NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)

HGVS:

NC_000008.11:g.38424690G>C
NG_007729.1:g.49145C>G
NM_001174063.2:c.755C>G
NM_001174064.2:c.731C>G
NM_001174065.2:c.749C>G
NM_001174066.2:c.488C>G
NM_001174067.2:c.848C>G
NM_001354367.2:c.749C>G
NM_001354368.2:c.482C>G
NM_001354369.2:c.749C>G
NM_001354370.2:c.482C>G
NM_015850.4:c.749C>G
NM_023105.3:c.488C>G
NM_023106.3:c.482C>G
NM_023110.3:c.755C>GMANE SELECT
NP_001167534.1:p.Pro252Arg
NP_001167535.1:p.Pro244Arg
NP_001167536.1:p.Pro250Arg
NP_001167537.1:p.Pro163Arg
NP_001167538.1:p.Pro283Arg
NP_001341296.1:p.Pro250Arg
NP_001341297.1:p.Pro161Arg
NP_001341298.1:p.Pro250Arg
NP_001341299.1:p.Pro161Arg
NP_056934.2:p.Pro250Arg
NP_075593.1:p.Pro163Arg
NP_075594.1:p.Pro161Arg
NP_075598.2:p.Pro252Arg
NP_075598.2:p.Pro252Arg
LRG_993t1:c.755C>G
LRG_993:g.49145C>G
LRG_993p1:p.Pro252Arg
NC_000008.10:g.38282208G>C
NM_023110.2:c.755C>G
NM_023110.3:c.755C>G
P11362:p.Pro252Arg

Protein change:

P161R; PRO252ARG

Links:

UniProtKB: P11362#VAR_004111; OMIM: 136350.0001; dbSNP: rs121909627

NCBI 1000 Genomes Browser:

rs121909627

Molecular consequence:

NM_001174063.2:c.755C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001174064.2:c.731C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001174065.2:c.749C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001174066.2:c.488C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001174067.2:c.848C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354367.2:c.749C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354368.2:c.482C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354369.2:c.749C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354370.2:c.482C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015850.4:c.749C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_023105.3:c.488C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_023106.3:c.482C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_023110.3:c.755C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypogonadotropic hypogonadism 2 with or without anosmia (HH2)
Synonyms:: Kallmann syndrome 2; HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA; HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007844; MedGen: C1563720; Orphanet: 478; OMIM: 147950

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
SCV000766219	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565, 10942429, 14613973, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000766219

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 1, 2023)

germline

clinical testing

PubMed (11)
[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 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

A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.

Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, Pulleyn LJ, Rutland P, Reardon W, Malcolm S, et al.

Nat Genet. 1994 Nov;8(3):269-74.

PubMed [citation]

PMID:: 7874169

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766219.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). This variant is present in population databases (rs121909627, gnomAD 0.0009%). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16279). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973).

#	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: Oct 8, 2024

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