4-1805644-C-G

Position:

• chr4-1805644-C-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1620C>G​(p.Asn540Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: 3.02

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 22 ACMG points.

• PS1: Transcript NM_000142.5 (FGFR3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain Protein kinase (size 289) in uniprot entity FGFR3_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) 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 chr4-1805643-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-1805644-C-G is Pathogenic according to our data. Variant chr4-1805644-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1805644-C-G is described in Lovd as [Pathogenic]. Variant chr4-1805644-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1620C>G	p.Asn540Lys	missense_variant	12/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1620C>G	p.Asn540Lys	missense_variant	12/18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460882 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	The FGFR3 c.1620C>G; p.Asn540Lys variant (rs28933068) is a recurrent alteration in patients with hypochondroplasia (Camera 2001, Kannu 2007, Korkmaz 2012, Linnankivi 2012, Xue 2014). Another variant at this position, c.1620C>A, also results in the same amino acid alteration (p.Asn540Lys), and is the most common pathogenic variant in hypochondroplasia patients (Xue 2014). Functional characterization of the variant protein indicates increased phosphorylation of ERK1/2, resulting in an over-activation of the MAPK signaling pathway (Krejci 2008). The c.1620C>G; p.Asn540Lys variant is reported in ClinVar (Variation ID: 16338). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, the p.Asn540Lys variant is considered to be pathogenic. References: Camera G et al. Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype. Am J Med Genet. 2001; 104(4):277-81. PMID: 11754059. Kannu P et al. FGFR3 mutations and medial temporal lobe dysgenesis. J Child Neurol. 2007; 22(2):211-3. PMID: 17621485. Korkmaz HA et al. Hypochondroplasia in a child with 1620C>G (Asn540Lys) mutation in FGFR3. J Clin Res Pediatr Endocrinol. 2012; 4(4):220-2. PMID: 23149434. Krejci P 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. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012; 158A(12):3119-25. PMID: 23165795. 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. PMID: 25614871. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	Observed in multiple individuals with hypochondroplasia in the published literature (Prinos et al., 1995; Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate this variant results in significantly reduced in vitro expression (Raffioni et al., 1998); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8640234, 29681095, 10360392, 22045636, 23149434, 9857065, 23165795, 11754059, 19088846, 8589686, 28777845, 29478821, 29150894, 17621485, 29620724, 30355600, 26380986, 34567078, 33942288, 32712949, 33389251) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	FGFR3: PS4, PM2, PM6, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypochondroplasia or achondroplasia (PMID: 7670477, 8589686, 9452043, 10360392, 11055896, 11754059, 23149434, 23165795, 25614871). ClinVar contains an entry for this variant (Variation ID: 16338). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -

Hypochondroplasia Pathogenic:9 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Sep 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.72). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016344 , VCV000016349 , VCV000374828 , VCV001325830). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	Most common pathogenic variant in hypochondroplasia -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	May 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 30, 2021	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 06, 2016	- -

Achondroplasia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2024	Variant summary: FGFR3 c.1620C>G (p.Asn540Lys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250610 control chromosomes (gnomAD). c.1620C>G has been reported in the literature in multiple individuals affected with Hypochondroplasia, in some cases as a de novo occurrence (e.g. Maddirevula_2018, Zhu_2022). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1619A>G, p.Asn540Ser), supporting the critical relevance of codon 540 to FGFR3 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 29620724, 35726512). ClinVar contains an entry for this variant (Variation ID: 16338). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PS2_Moderate+PS3_Moderate+PS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2016

- -

FGFR3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The FGFR3 c.1620C>G variant is predicted to result in the amino acid substitution p.Asn540Lys. This variant has been reported to be the most common cause of hypochondroplasia (Bellus et al. 1995. PubMed ID: 7670477; Prinos et al. 1995. PubMed ID: 8589686). Additionally, functional studies support its pathogenicity (Raffioni et al. 1998. PubMed ID: 9857065). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Larsen syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Dec 25, 2021

- -

Short stature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 23, 2015

- -

Connective tissue disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-0.10	N;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		1.0
MutPred		0.90		Gain of methylation at N540 (P = 0.007);.;.;.;.;
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.81

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: rs28933068; hg19: chr4-1807371;