chr4-1804362-G-T

Variant names:

• chr4-1804362-G-T
• rs121913479
• NM_000142.5:c.1108G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1108G>T​(p.Gly370Cys) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G370S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 2.49

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 4-1804362-G-T is Pathogenic according to our data. Variant chr4-1804362-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804362-G-T is described in Lovd as [Pathogenic]. Variant chr4-1804362-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1108G>T	p.Gly370Cys	missense_variant	Exon 9 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1108G>T	p.Gly370Cys	missense_variant	Exon 9 of 18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Nov 24, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.(G370C) results in spontaneous disulfide bond-mediated dimerization of the FGFR3 protein independent of ligand stimulation that subsequently leads to constitutive activation of the receptor (Adar et al., 2002; You et al., 2007); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8845844, 15772091, 10471491, 25157968, 9790257, 12009017, 16841094, 19752524, 25728633, 25614871, 27028100, 28249712, 28254233, 10696568, 11745189, 24863959, 20301540, 19381019, 17845056) -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 370 of the FGFR3 protein (p.Gly370Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thanatophoric dysplasia type 1 (PMID: 8845844, 9790257, 24863959, 25614871). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16359). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 12009017). For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR3 c.1108G>T; p.Gly370Cys variant (rs121913479) has been described in several individuals with thanatophoric dysplasia (TD), type I (Rousseau 1996, Katsumata 1998, Xue 2014). It is reported as pathogenic in ClinVar (Variation ID: 16359) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional studies have indicated the p.Gly370Cys variant promotes ligand-independent FGFR3 correct spatial dimerization that results in constitutive ligand independent phosphorylation of MAPK and c-fos transcription (Adar 2002). Based on available formation, this variant is considered pathogenic. REFERENCES Adar R et al. Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. J Bone Miner Res. 2002;17(5): 860-868. Katsumata N et al. G370C mutation in the FGFR3 gene in a Japanese patient with thanatophoric dysplasia. Endocrin J 1998; 45 Suppl:S171-S174. Rousseau F et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet 1996; 5(4):509-512. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med 2014; 2(6): 497-503. -

Jun 13, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thanatophoric dysplasia type 1 Pathogenic:3 Other:1

Jul 06, 2019

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 05, 2022

Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thanatophoric dysplasia Pathogenic:1

Jan 10, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Epidermal nevus Pathogenic:1

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Achondroplasia Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer;C5774286:Lacrimoauriculodentodigital syndrome 2 Pathogenic:1

Jan 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Uncertain	0.80	D;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.083	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0060	B;D;B
Vest4		0.83
MutPred		0.81		Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;
MVP		0.88
MPC		0.31
ClinPred		0.58	D
GERP RS		2.7
Varity_R		0.25
gMVP		0.69

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: rs121913479; hg19: chr4-1806089; COSMIC: COSV53390089; COSMIC: COSV53390089;