This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000142.5(FGFR3):c.2421A>G (p.Ter807Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000142.5(FGFR3):c.2421A>G (p.Ter807Trp)
Variation ID: 65564 Accession: VCV000065564.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1807262 (GRCh38) [ NCBI UCSC ] 4: 1808989 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2013 Oct 13, 2024 Sep 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000142.5:c.2421A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000133.1:p.Ter807Trp stop lost NM_001163213.1:c.2427A>G NM_001163213.2:c.2427A>G NP_001156685.1:p.Ter809Trp stop lost NM_001354809.2:c.2424A>G NP_001341738.1:p.Ter808Trp stop lost NM_001354810.2:c.2353A>G NP_001341739.1:p.Lys785Glu missense NM_022965.4:c.2085A>G NP_075254.1:p.Ter695Trp stop lost NR_148971.2:n.2847A>G non-coding transcript variant NC_000004.12:g.1807262A>G NC_000004.11:g.1808989A>G NG_012632.1:g.18951A>G LRG_1021:g.18951A>G LRG_1021t1:c.2421A>G LRG_1021p1:p.Ter807Trp - Protein change
- K785E
- Other names
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*807delinsTrpArgA
*807W
*809W
*695W
*808W
- Canonical SPDI
- NC_000004.12:1807261:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FGFR3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
976 | 1126 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 19, 2022 | RCV000055766.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 13, 2024 | RCV001569868.14 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2024 | RCV004760363.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Apr 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Thanatophoric dysplasia type 1
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000992335.1
First in ClinVar: Sep 11, 2019 Last updated: Sep 11, 2019 |
Comment:
This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results … (more)
This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic. (less)
|
|
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Pathogenic
(Oct 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001832258.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
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Likely pathogenic
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Thanatophoric dysplasia type 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579214.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS1, PM4, PM2_SUP
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Number of individuals with the variant: 1
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Pathogenic
(Jul 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002507664.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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 individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). This variant is also known as p.X807Trp. ClinVar contains an entry for this variant (Variation ID: 65564). 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: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Achondroplasia
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374306.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
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Pathogenic
(Jun 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001794029.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024 |
Comment:
Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a … (more)
Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384) (less)
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not provided
(-)
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no classification provided
Method: literature only
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Thanatophoric dysplasia type 1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086715.2
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
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 individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). This variant is also known as p.X807Trp. ClinVar contains an entry for this variant (Variation ID: 65564). 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: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic.
Comment:
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 individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). This variant is also known as p.X807Trp. ClinVar contains an entry for this variant (Variation ID: 65564). 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: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Thanatophoric Dysplasia. | Adam MP | - | 2023 | PMID: 20301540 |
| Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach. | Chitty LS | Prenatal diagnosis | 2015 | PMID: 25728633 |
| FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. | Xue Y | Molecular genetics & genomic medicine | 2014 | PMID: 25614871 |
| The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. | Bonaventure J | The FEBS journal | 2007 | PMID: 17509076 |
| Clinical spectrum of fibroblast growth factor receptor mutations. | Passos-Bueno MR | Human mutation | 1999 | PMID: 10425034 |
| Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. | Rousseau F | Nature genetics | 1995 | PMID: 7647778 |
Text-mined citations for rs121913103 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.