rs1554570706

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_023110.3(FGFR1):​c.232C>T​(p.Arg78Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

FGFR1
NM_023110.3 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.53
Variant links:
Genes affected
FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
In a disulfide_bond (size 46) in uniprot entity FGFR1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_023110.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.893
PP5
Variant 8-38429808-G-A is Pathogenic according to our data. Variant chr8-38429808-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38429808-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR1NM_023110.3 linkc.232C>T p.Arg78Cys missense_variant Exon 3 of 18 ENST00000447712.7 NP_075598.2 P11362-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGFR1ENST00000447712.7 linkc.232C>T p.Arg78Cys missense_variant Exon 3 of 18 1 NM_023110.3 ENSP00000400162.2 P11362-1
FGFR1ENST00000397091.9 linkc.232C>T p.Arg78Cys missense_variant Exon 3 of 18 1 ENSP00000380280.5 P11362-7
FGFR1ENST00000397108.8 linkc.232C>T p.Arg78Cys missense_variant Exon 4 of 19 1 ENSP00000380297.4 P11362-7
FGFR1ENST00000397113.6 linkc.232C>T p.Arg78Cys missense_variant Exon 3 of 18 2 ENSP00000380302.2 P11362-7
FGFR1ENST00000356207.9 linkc.92-1373C>T intron_variant Intron 2 of 16 1 ENSP00000348537.5 P11362-3
FGFR1ENST00000397103.5 linkc.92-1373C>T intron_variant Intron 1 of 15 5 ENSP00000380292.1 E7EU09
FGFR1ENST00000326324.10 linkc.92-1373C>T intron_variant Intron 2 of 16 1 ENSP00000327229.6 P11362-14
FGFR1ENST00000487647.5 linkn.92-418C>T intron_variant Intron 1 of 11 1 ENSP00000435254.1 E9PKX3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2
Aug 27, 2019
Genetics Department, Polish Mother's Memorial Hospital Research Institute
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

May 04, 2023
Reproductive Endocrine Unit, Massachusetts General Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

FGFR1-related disorder Pathogenic:1
Dec 29, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The FGFR1 c.232C>T variant is predicted to result in the amino acid substitution p.Arg78Cys. This variant has been reported in multiple individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Pitteloud et al. 2006. PubMed ID: 16764984; Miraoui H et al. 2013. PubMed ID: 23643382; Xu C et al. 2017. PubMed ID: 28754744; Cassatella D et al. 2018. PubMed ID: 29419413; Gach A et al. 2020. PubMed ID: 31996231; Liu Q et al. 2022. PubMed ID: 35090434). In at least one individual, this variant was found to have arisen de novo (Liu Q et al. 2022. PubMed ID: 35090434). One functional study showed that this variant evoked a decreased response (Xu C et al. 2017. PubMed ID: 28754744). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1
Mar 31, 2025
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.331C>T, p.(R111C); This variant is associated with the following publications: (PMID: 23643382, 16764984, 28754744, 31996231, 35090434, 34348883, 23329143, 29419413, 37805574) -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1
Apr 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 78 of the FGFR1 protein (p.Arg78Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypogonadotropic hypogonadism and Kallmann syndrome (PMID: 16764984, 23643382, 28754744; Invitae). ClinVar contains an entry for this variant (Variation ID: 431966). 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%. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 28754744). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.57
.;.;D;.;.;.;.;.;T;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.97
D;.;D;D;D;.;D;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Pathogenic
3.3
.;M;M;.;M;M;.;M;.;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;.;.
Polyphen
1.0
D;D;D;.;D;D;D;D;.;.
Vest4
0.84
MutPred
0.75
.;Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);.;Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);
MVP
0.88
MPC
0.23
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.87
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554570706; hg19: chr8-38287326; COSMIC: COSV58343389; COSMIC: COSV58343389; API