8-38414599-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_023110.3(FGFR1):c.2008G>A(p.Glu670Lys) 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 30)

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 6.16

Publications

12 publications found

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]

FGFR1 Gene-Disease associations (from GenCC):

encephalocraniocutaneous lipomatosis
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hartsfield-Bixler-Demyer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
hypogonadotropic hypogonadism 2 with or without anosmia
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
osteoglophonic dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Pfeiffer syndrome type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Jackson-Weiss syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated trigonocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism 2 with or without anosmia, osteoglophonic dysplasia, isolated trigonocephaly, septooptic dysplasia, Pfeiffer syndrome, tooth agenesis, hypogonadotropic hypogonadism, Kallmann syndrome, holoprosencephaly, Jackson-Weiss syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 8-38414599-C-T is Pathogenic according to our data. Variant chr8-38414599-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 50852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.2008G>A	p.Glu670Lys	missense_variant	Exon 15 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR1	ENST00000447712.7 link	c.2008G>A	p.Glu670Lys	missense_variant	Exon 15 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9 link	c.2002G>A	p.Glu668Lys	missense_variant	Exon 15 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8 link	c.2002G>A	p.Glu668Lys	missense_variant	Exon 16 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6 link	c.2002G>A	p.Glu668Lys	missense_variant	Exon 15 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9 link	c.1741G>A	p.Glu581Lys	missense_variant	Exon 14 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5 link	c.1741G>A	p.Glu581Lys	missense_variant	Exon 13 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10 link	c.1735G>A	p.Glu579Lys	missense_variant	Exon 14 of 17	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FGFR1-related disorder

Pathogenic:1

Aug 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FGFR1 c.2008G>A variant is predicted to result in the amino acid substitution p.Glu670Lys. This variant has been reported in several individuals with Kallmann syndrome or hypogonadotropic hypogonadism (see, for example, Costa-Barbosa et al. 2013. PubMed ID: 23533228; Miraoui et al. 2013. PubMed ID: 23643382; Nie et al. 2021. PubMed ID: 33548149). It occurred de novo in multiple individuals (Hou et al. 2020. PubMed ID: 32520725; Ying et al. 2020. PubMed ID: 33299522; Liu et al. 2022. PubMed ID: 35090434). In vitro functional studies showed that this variant induces posttranslational modification defects, leading to impairment of the receptor and abnormal signaling (Ying et al. 2020. PubMed ID: 33299522). This variant has not been reported in a large population database, indicating it is rare. Another variant affecting the same amino acid (p.Glu670Ala) has also been reported in individuals with hypogonadotropic hypogonadism (Laitinen et al. 2011. PubMed ID: 21682876). This variant is interpreted as pathogenic. -

Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The variant has been classified as P2 based on the variant meeting the following ACMG Criteria: PS2,PM2,PP3,PP1,PP2,PP4. -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 670 of the FGFR1 protein (p.Glu670Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kallmann syndrome (PMID: 23533228, 31200363, 32520725). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50852). 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%. For these reasons, this variant has been classified as Pathogenic. -

Hypogonadotropic hypogonadism 2 with anosmia

Other:1

May 02, 2013

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;D;.;.;.;.;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;.;D;D;.;D;D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;.;H;.;.;.;.;.;.;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0080

D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;.;D;D;.;.

Vest4

0.96

MutPred

0.90

.;.;Gain of methylation at E670 (P = 0.0144);.;.;.;.;.;.;.;

MVP

0.97

MPC

2.2

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

1.0

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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