4-1804372-A-G

Position:

• chr4-1804372-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1118A>G​(p.Tyr373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 3.54

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist 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 acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-1804372-A-G is Pathogenic according to our data. Variant chr4-1804372-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 16342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804372-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1118A>G	p.Tyr373Cys	missense_variant	9/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1118A>G	p.Tyr373Cys	missense_variant	9/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.00154 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 13, 2023	The FGFR3 c.1118A>G; p.Tyr373Cys variant (rs121913485) is reported in the literature in multiple individuals affected with thanatophoric dwarfism (Brodie 1999, Rousseau 1996), and it was identified in a cohort of fetal skeletal dysplasia patients (Carass 2014). This variant is reported in ClinVar (Variation ID: 16342), and it is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Carass et al. found the p.Tyr373Cys variant to be de novo in a male fetus with features consistent with lethal skeletal dysplasia. Furthermore, a mouse model of the p.Tyr373Cys variant displays features similar to achondroplasia (Di Rocco 2014, Lorget 2012) and in vitro studies performed on the p.Tyr373Cys variant in human chondrocytes show decreased proliferation (Krejci 2008). The tyrosine at codon 373 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.800). Based on available information, this variant is considered to be pathogenic. References: Brodie SG et al. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999 Jun 11;84(5):476-80. PMID: 10360402. Carss et al. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014; 23(12):3269-3277. PMID: 24476948. Di Rocco et al. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet. 2014; 23(11):2914-2925. PMID: 24419316. Krejci et al. Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage. PLoS One. 2008;3(12):e3961. PMID: 19088846. Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012 Dec 7;91(6):1108-14. PMID: 23200862. Rousseau et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996; 5(4):509-512. PMID: 8845844. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2020	Published functional studies indicate that the Y373C variant causes increased activation of the receptor in the absence of the ligand (Ronchetti et al., 2001; Qi et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21273588, 19331127, 11851976, 9843049, 30692697, 8845844, 30712878, 25606676, 24419316, 24476948, 22045636, 11429702, 24657641, 19088846, 23200862, 17509076, 17320202, 14715624, 11526491, 26858415, 29593476, 28249712, 19789973, 9438390, 31299979) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 20, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FGFR3 protein (p.Tyr373Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846, 23200862, 24419316, 25606676). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function. ClinVar contains an entry for this variant (Variation ID: 16342). This missense change has been observed in individual(s) with thanatophoric dysplasia (PMID: 8845844, 24476948, 25614871, 28249712). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 25, 2017	- -

Thanatophoric dysplasia type 1 Pathogenic:6 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 22, 2021	The FGFR3 c.1118A>G variant is a single nucleotide change in exon 9/18 of the FGFR3 gene, which is predicted to change the amino acid tyrosine at position 373 in the protein to cysteine. This variant has been identified as a de novo variant in this patient (PS2). This variant is absent from population databases (PM2), but has been reported numerous times in the literature in association with Thanatophoric dwarfism and Achondroplasia (e.g. PMID: 8845844, 24476948, 28249712) (PS4). It is the second most common cause of this condition (PMID:25614871). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16342) and is listed in HGMD as disease causing (CM960657). Computational predictions support a deleterious effect on the gene or gene product (PP3). Functional studies reproducing the equivalent variant in mouse models mirrored the clinical presentation seen in humans (Lorget et al 2012 PMID: 23200862) (PS3). -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Apr 16, 2021	- -

Papillary renal cell carcinoma, sporadic Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Myeloproliferative disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

See cases Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University

Aug 20, 2021

- -

Urinary bladder carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.084
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.86
MutPred		0.85		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;
MVP		0.96
MPC		0.99
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.62
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913485; hg19: chr4-1806099; COSMIC: COSV53390174; COSMIC: COSV53390174;