4-1806162-A-G
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_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. K650T) has been classified as Pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
Publications
- achondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Crouzon syndrome-acanthosis nigricans syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
- hypochondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- lacrimoauriculodentodigital syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Muenke syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
- thanatophoric dysplasia type 1Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
- thanatophoric dysplasia type 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- camptodactyly-tall stature-scoliosis-hearing loss syndromeInheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- severe achondroplasia-developmental delay-acanthosis nigricans syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- isolated brachycephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated plagiocephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndrome 1Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000142.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | MANE Select | c.1948A>G | p.Lys650Glu | missense | Exon 14 of 18 | NP_000133.1 | ||
| FGFR3 | NM_001163213.2 | c.1954A>G | p.Lys652Glu | missense | Exon 14 of 18 | NP_001156685.1 | |||
| FGFR3 | NM_001354809.2 | c.1951A>G | p.Lys651Glu | missense | Exon 14 of 18 | NP_001341738.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | TSL:5 MANE Select | c.1948A>G | p.Lys650Glu | missense | Exon 14 of 18 | ENSP00000414914.2 | ||
| FGFR3 | ENST00000481110.7 | TSL:1 | c.1951A>G | p.Lys651Glu | missense | Exon 14 of 17 | ENSP00000420533.2 | ||
| FGFR3 | ENST00000352904.6 | TSL:1 | c.1612A>G | p.Lys538Glu | missense | Exon 11 of 15 | ENSP00000231803.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:8
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.
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)
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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 16331). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FGFR3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846). 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. For these reasons, this variant has been classified as Pathogenic.
Thanatophoric dysplasia, type 2 Pathogenic:5Other:1
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
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).
ACMG codes: PS2, PS3, PS4, PM2, PP3, PP4, PP5
Thanatophoric dysplasia type 1 Pathogenic:1
Thanatophoric dysplasia Pathogenic:1
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
See cases Pathogenic:1
FGFR3-related disorder Pathogenic:1
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.
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
Spermatocytic seminoma Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at