NM_023110.3(FGFR1):c.2266C>T (p.Arg756Cys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 11, 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:: RCV002982931.3

Allele description [Variation Report for NM_023110.3(FGFR1):c.2266C>T (p.Arg756Cys)]

NM_023110.3(FGFR1):c.2266C>T (p.Arg756Cys)

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.2266C>T (p.Arg756Cys)

HGVS:

NC_000008.11:g.38413944G>A
NG_007729.1:g.59891C>T
NM_000604.2:c.2266C>T
NM_001174063.2:c.2260C>T
NM_001174064.2:c.2236C>T
NM_001174065.2:c.2260C>T
NM_001174066.2:c.1999C>T
NM_001174067.2:c.2359C>T
NM_001354367.2:c.2260C>T
NM_001354368.2:c.1987C>T
NM_001354369.2:c.2254C>T
NM_001354370.2:c.1993C>T
NM_001410922.1:c.2254C>T
NM_015850.4:c.2260C>T
NM_023105.3:c.1999C>T
NM_023106.3:c.1993C>T
NM_023110.3:c.2266C>TMANE SELECT
NP_000595.1:p.Arg756Cys
NP_001167534.1:p.Arg754Cys
NP_001167535.1:p.Arg746Cys
NP_001167536.1:p.Arg754Cys
NP_001167537.1:p.Arg667Cys
NP_001167538.1:p.Arg787Cys
NP_001341296.1:p.Arg754Cys
NP_001341297.1:p.Arg663Cys
NP_001341298.1:p.Arg752Cys
NP_001341299.1:p.Arg665Cys
NP_001397851.1:p.Arg752Cys
NP_056934.2:p.Arg754Cys
NP_075593.1:p.Arg667Cys
NP_075594.1:p.Arg665Cys
NP_075598.2:p.Arg756Cys
NP_075598.2:p.Arg756Cys
LRG_993t1:c.2266C>T
LRG_993:g.59891C>T
LRG_993p1:p.Arg756Cys
NC_000008.10:g.38271462G>A
NM_023110.2:c.2266C>T

Protein change:

R663C

Molecular consequence:

NM_000604.2:c.2266C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174063.2:c.2260C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174064.2:c.2236C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174065.2:c.2260C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174066.2:c.1999C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174067.2:c.2359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354367.2:c.2260C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354368.2:c.1987C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354369.2:c.2254C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354370.2:c.1993C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001410922.1:c.2254C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015850.4:c.2260C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_023105.3:c.1999C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_023106.3:c.1993C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_023110.3:c.2266C>T - 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

Recent activity

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Mus musculus mitogen-activated protein kinase 10 (Mapk10), transcript variant 4,...
Mus musculus mitogen-activated protein kinase 10 (Mapk10), transcript variant 4, mRNA
gi|2249006996|ref|NM_001310685.2|

Nucleotide
Nematonereis unicornis A JZ-2010 voucher USNM1122623 18S ribosomal RNA gene, par...
Nematonereis unicornis A JZ-2010 voucher USNM1122623 18S ribosomal RNA gene, partial sequence
gi|296885157|gb|GQ497519.1|

Nucleotide
C1orf175 (0)
GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003295069	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27246988, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003295069

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 11, 2023)

germline

clinical testing

PubMed (2)
[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

Targeted next-generation sequencing reveals multiple deleterious variants in OPLL-associated genes.

Chen X, Guo J, Cai T, Zhang F, Pan S, Zhang L, Wang S, Zhou F, Diao Y, Zhao Y, Chen Z, Liu X, Chen Z, Liu Z, Sun Y, Du J.

Sci Rep. 2016 Jun 1;6:26962. doi: 10.1038/srep26962.

PubMed [citation]

PMID:: 27246988
PMCID:: PMC4887887

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003295069.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 756 of the FGFR1 protein (p.Arg756Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with ossification of the posterior longitudinal ligament of the spine (PMID: 27246988). This variant is also known as p.R754C. ClinVar contains an entry for this variant (Variation ID: 2079731). 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 FGFR1 protein function with a positive predictive value of 95%. 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.

#	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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