rs1554570706

chr8-38429808-G-Achr8-38429808-G-Cchr8-38429808-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FGFR1
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431966.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}. Variant chr8-38429808-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR1	NM_023110.3	c.232C>T	p.Arg78Cys	missense_variant	3/18	ENST00000447712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR1	ENST00000447712.7	c.232C>T	p.Arg78Cys	missense_variant	3/18	1	NM_023110.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

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, criteria provided, single submitter

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. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2017

The R78C variant in the FGFR1 gene has been published previously in association with Kallmann syndrome; however, no detailed segregation information was provided (Pitteloud et al., 2006; Miraoui et al., 2013). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R78C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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
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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
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;