4-1806162-A-G

Position:

• chr4-1806162-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1948A>G​(p.Lys650Glu) variant causes a missense change involving the alteration of a 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. K650M) has been classified 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: 9.01

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]

FGFR3 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a mutagenesis_site Constitutively activated kinase. (size 0) in uniprot entity FGFR3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1806163-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 4-1806162-A-G is Pathogenic according to our data. Variant chr4-1806162-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 16331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1806162-A-G is described in Lovd as [Pathogenic]. Variant chr4-1806162-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1948A>G	p.Lys650Glu	missense_variant	14/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1948A>G	p.Lys650Glu	missense_variant	14/18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 09, 2020	The FGFR3 c.1948A>G; p.Lys650Glu variant (rs78311289) is reported in the literature as a de novo variant in multiple individuals affected with thanatophoric dysplasia type II (Tavormina 1995, Tonni 2014, Xue 2014). This variant is reported in ClinVar (Variation ID: 16331), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 650 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a gain of function leading to constitutive activation (Huang 2013, Livens 2003). Additionally, other amino acid substitutions at this codon (Met, Asn, Gln, Thr) have been reported in individuals with skeletal dysplasias and are considered pathogenic (Bellus 2000). Based on available information, this variant is considered to be pathogenic. References: Bellus GA et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000 Dec;67(6):1411-21. Huang Z et al. Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation. Structure 2013 21(10):1889-1896. Lievens PM and Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem 2003 278:17344-17349. Tavormina PL et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 1995 9(3):321-328. Tonni G et al. Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: early ultrasound markers of de novo thanatophoric dysplasia type II with cloverleaf skull (Kleeblattschaedel). Congenit Anom (Kyoto) 2014 4(4):228-232. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 28, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	The p.(K650E) variant is reported to be exclusively associated with thanatophoric dysplasia type II (Trujillo-Tiebas et al., 2009; Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate that the variant results in constitutive autophosphorylation and activation of the FGF receptor (Otsuka et al., 2011; Webster et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21204232, 24517215, 31994750, 23972473, 19855393, 12461689, 19789973, 15843401, 22843502, 9857065, 19088846, 11241532, 24075385, 11406607, 11055896, 10918587, 9315632, 21273588, 7773297, 30692697, 30132994, 29458880, 33942288, 22045636) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.650Lys amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11055896, 16912704, 20453470, 21510009). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16331). This missense change has been observed in individual(s) with thanatophoric dysplasia (PMID: 7773297, 11241532, 24075385). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 650 of the FGFR3 protein (p.Lys650Glu). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 24, 2022	- -

Thanatophoric dysplasia, type 2 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Moderate+PM5_Strong+PM6_Supporting+PS4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 04, 2023	The FGFR3 c.1948A>G variant is classified as PATHOGENIC (PS4, PS2, PS3, PP3) The FGFR3 c.1948A>G variant is a single nucleotide change in exon 14/18 of the FGFR3 gene, which is predicted to change the amino acid lysine at position 650 in the protein to glutamic acid. This recurrent variant is identified in >99% of individuals with Thanophoric dysplasia type II (PS4). This variant has been identified as a de novo variant in multiple individuals in the literature (PMID:31994750, PMID:34930662, PMID:20704477, PMID:25614871) (PS2). This variant is absent from population databases. Well-established functional studies show a deleterious effect of this variant (PMID:19088846, PMID:23972473, PMID:15843401, PMID:21273588, PMID:8599935) (PS3). Other variants that disrupt this residue have been determined to be pathogenic (PMID:11055896, PMID:16912704, PMID:20453470, PMID:21510009). Computational predictions support a deleterious effect on the gene or gene product (PP3). Thise variant has been reported in dbSNP (rs78311289) and in the HGMD database: CM950476. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16331). -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 23, 2020	ACMG codes: PS2, PS3, PS4, PM2, PP3, PP4, PP5 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -

Thanatophoric dysplasia type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam

Jun 22, 2022

- -

Thanatophoric dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 16, 2023

Variant summary: FGFR3 c.1948A>G (p.Lys650Glu) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein catalytic kinase domain (IPR001245) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249076 control chromosomes in gnomAD. c.1948A>G has been reported in the literature in multiple individuals affected with Thanatophoric Dysplasia, including multiple de novo occurrences (example: Tavormina_1995, Xue_2014, Zhang_2021, Bowling_2022). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits profound in vitro kinase activation (example: Webster_1996, Tavormina_1999). Other variants at the Lys650 residue have been reported as associated with disease (p.Lys650Met/Gln/Thr/Asn), suggesting that this amino acid residue is functionally important (Bellus_2000). The following publications have been ascertained in the context of this evaluation (PMID: 11055896, 34930662, 10053006, 7773297, 8754806, 25614871, 33942288). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Multiple myeloma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

See cases Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Feb 10, 2022

- -

FGFR3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The FGFR3 c.1948A>G variant is predicted to result in the amino acid substitution p.Lys650Glu. This variant has been reported to be causative for thanatophoric dysplasia (Tavormina et al. 1995. PubMed ID: 7773297; Wilcox et al. 1998. PubMed ID: 9677066). In addition, similar variants affecting the same amino acid (p.Lys650Asn, p.Lys650Gln, p.Lys650Thr, p.Lys650Met) have been documented to be pathogenic for FGFR3-related disorders (Human Gene Mutation Database, https://portal.biobase-international.com/hgmd). The c.1948A>G (p.Lys650Glu) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Spermatocytic seminoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.82	L;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.93
MutPred		0.98		Gain of ubiquitination at K649 (P = 0.0328);.;.;.;.;
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.83

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: rs78311289; hg19: chr4-1807889; COSMIC: COSV53390625; COSMIC: COSV53390625;