rs1554570706

Positions:

• chr8-38429808-G-A
• chr8-38429808-G-C
• chr8-38429808-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.53

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 (HGNC:):

ACMG classification

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 gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.232C>T	p.Arg78Cys	missense_variant	3/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.232C>T	p.Arg78Cys	missense_variant	3/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.232C>T	p.Arg78Cys	missense_variant	3/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.232C>T	p.Arg78Cys	missense_variant	4/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.232C>T	p.Arg78Cys	missense_variant	3/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-1373C>T		intron_variant		1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-1373C>T		intron_variant		5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-1373C>T		intron_variant		1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.92-418C>T		intron_variant		1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Reproductive Endocrine Unit, Massachusetts General Hospital	May 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Genetics Department, Polish Mother's Memorial Hospital Research Institute	Aug 27, 2019	- -

FGFR1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2024

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) -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2018

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies in myoblast cells have shown that this missense change, p.Arg78Cys, exhibits a decrease in response to FGF21 compared to cells without this variant (PMID: 28754744). This variant has been reported in a family with Kallmann syndrome (PMID: 16764984) and several individuals with hypogonadotropic hypogonadism (PMID: 16764984, 23643382, 28754744, Invitae). ClinVar contains an entry for this variant (Variation ID: 431966). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 78 of the FGFR1 protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

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

Other links and lift over

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