4-1807261-G-C

Variant names:

• chr4-1807261-G-C
• rs397515514
• NM_000142.5:c.2420G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000142.5(FGFR3):​c.2420G>C​(p.Ter807Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.86
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• achondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Crouzon syndrome-acanthosis nigricans syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• hypochondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• lacrimoauriculodentodigital syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Muenke syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• thanatophoric dysplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
• thanatophoric dysplasia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• camptodactyly-tall stature-scoliosis-hearing loss syndrome

  Inheritance: 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 syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000142.5 Downstream stopcodon found after 897 codons.
• PP5: Variant 4-1807261-G-C is Pathogenic according to our data. Variant chr4-1807261-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 994395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.2420G>C	p.Ter807Serext*?	stop_lost	Exon 18 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.2420G>C	p.Ter807Serext*?	stop_lost	Exon 18 of 18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 21, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in unrelated patients with thanatophoric dysplasia in published literature (Chen et al., 2017; Gomes et al., 2018); Variant resulting in loss of the termination codon leading to protein extension by 101 amino acids; Several different variants resulting in similar protein extensions have been reported in the Human Gene Mutation Database associated with thanatophoric dysplasia (HGMD), and have apparently similar functional consequences on protein stability and/or processing (Bonaventure et al., 2007; Gibbs et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18923003, 17507011, 18328977, 25728633, 25614871, 30048571, 29593476, 31299979, 17509076, 17320202, 28254233) -

Apr 23, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR3 c.2420G>C; p.Ter807SerextTer101 variant is reported in the literature in multiple individuals affected with thanatophoric dysplasia type I (TD1) or a related skeletal dysplasia (Gomes 2018, Liu 2019, Xue 2014). In at least one instance, the variant was not found in either parent of an affected individual, suggesting a de novo origin (Liu 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes loss of the canonical stop codon and extension of the protein by 101 amino acids. Other stop-loss variants in FGFR3 have been reported in individuals with TD1 or a related skeletal dysplasia and are considered disease-causing (Gomes 2018, Passos-Bueno 1999, Xue 2014). Based on available information, the p.Ter807SerextTer101 variant is considered to be pathogenic. References: Gomes MES et al. Novel and Recurrent Mutations in the FGFR3 Gene and Double Heterozygosity Cases in a Cohort of Brazilian Patients with Skeletal Dysplasia. Mol Syndromol. 2018 Feb;9(2):92-99. Liu Y et al. Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. Diagn Pathol. 2019 Jul 13;14(1):76. Passos-Bueno MR et al. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 1999;14(2):115-25. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014 Nov;2(6):497-503. -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 994395). This sequence change disrupts the translational stop signal of the FGFR3 mRNA. It is expected to extend the length of the FGFR3 protein by 101 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with achrondoplasia and/or thanatophoric dysplasia type I (PMID: 29593476, 31299979). In at least one individual the variant was observed to be de novo. This variant is also known as c.2426G>C (p.X809S,101) or X807Ser or *807S. This variant results in an extension of the FGFR3 protein. Other variant(s) that result in a similarly extended protein product (p.*807Leuext*101) have been determined to be pathogenic (PMID: 33942288). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

FGFR3-related disorder Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGFR3 c.2420G>C variant is predicted to result in extension of the open reading frame (p.*807Serext*101). This variant has been reported to be causative for thanatophoric dysplasia (reported as Term807Ser in Figure 5, Baujat et al. 2008. PubMed ID: 18328977; reported as c.2426G>C, p.X809S,101 using NM_001163213.1, Liu et al. 2019. PubMed ID: 31299979). In addition, other variants affecting the same codon (*807) have been reported as causative for thanatophoric dysplasia (Rousseau et al. 1995. PubMed ID: 7647778; Passos-Bueno et al. 1999. PubMed ID: 10425034; Baujat et al. 2008. PubMed ID: 18328977; Foldynova-Trantirkova et al. 2012. PubMed ID: 22045636; Xue et al. 2014. PubMed ID: 25614871). In summary, we interpret this variant as pathogenic. -

Thanatophoric dysplasia, type 2;C1868678:Thanatophoric dysplasia type 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM4+PS4_Moderate+PM6_Strong+PP4 -

Connective tissue disorder Pathogenic:1

Jun 01, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.84
Eigen	Pathogenic	0.88
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		2.9
Vest4		0.35
GERP RS		3.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515514; hg19: chr4-1808988; COSMIC: COSV104592988; COSMIC: COSV104592988;