ClinVar Genomic variation as it relates to human health
NM_000142.5(FGFR3):c.835A>T (p.Ser279Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000142.5(FGFR3):c.835A>T (p.Ser279Cys)
Variation ID: 16356 Accession: VCV000016356.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1801930 (GRCh38) [ NCBI UCSC ] 4: 1803657 (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 Apr 4, 2013 Feb 14, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000142.5:c.835A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000133.1:p.Ser279Cys missense NM_001163213.2:c.835A>T NP_001156685.1:p.Ser279Cys missense NM_001354809.2:c.835A>T NP_001341738.1:p.Ser279Cys missense NM_001354810.2:c.835A>T NP_001341739.1:p.Ser279Cys missense NM_022965.4:c.835A>T NP_075254.1:p.Ser279Cys missense NR_148971.2:n.1110A>T non-coding transcript variant NC_000004.12:g.1801930A>T NC_000004.11:g.1803657A>T NG_012632.1:g.13619A>T LRG_1021:g.13619A>T LRG_1021t1:c.835A>T - Protein change
- S279C
- Other names
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- Canonical SPDI
- NC_000004.12:1801929:A:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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FGFR3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
939 | 1086 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Jun 3, 2020 | RCV000017766.29 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2008 | RCV000017767.28 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000730955.11 |
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
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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
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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
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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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Pathogenic
(Dec 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000858723.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jun 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Achondroplasia
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001524467.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(Jun 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002538896.2
First in ClinVar: Jul 01, 2022 Last updated: Mar 04, 2023 |
Comment:
Observed in other patients with achondroplasia or hypochondroplasia in published literature and in a patient referred for genetic testing at GeneDx (Shelmerdine et al., 2016; … (more)
Observed in other patients with achondroplasia or hypochondroplasia in published literature and in a patient referred for genetic testing at GeneDx (Shelmerdine et al., 2016; Friez et al., 2008); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27257098, 19802676, 27028100, 26224133, Ahn[atricle]2016, 32227640, 25728633, 16912704, 17895900) (less)
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002507590.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the FGFR3 protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the FGFR3 protein (p.Ser279Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with achondroplasia (PMID: 16912704). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16356). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2008)
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no assertion criteria provided
Method: literature only
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ACHONDROPLASIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038044.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a boy with achondroplasia (100800) who was negative for the common G380R mutation (134934.0001), Heuertz et al. (2006) identified heterozygosity for a de novo … (more)
In a boy with achondroplasia (100800) who was negative for the common G380R mutation (134934.0001), Heuertz et al. (2006) identified heterozygosity for a de novo 835A-C transversion in exon 7 of the FGFR3 gene, resulting in an ser279-to-cys (S279C) substitution in the IgIIIa extracellular domain. In addition to the typical skeletal features of ACH, the child had epilepsy and moderate learning difficulties. Severe kyphoscoliosis required surgical correction at age 7 years, which was complicated by postoperative lower limb paralysis requiring decompressive surgery. Friez and Wilson (2008) identified the S279C mutation in a newborn originally diagnosed with achondroplasia whose phenotype evolved into a milder form of hypochondroplasia (146000) in early childhood. (less)
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Pathogenic
(Mar 01, 2008)
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no assertion criteria provided
Method: literature only
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HYPOCHONDROPLASIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038045.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a boy with achondroplasia (100800) who was negative for the common G380R mutation (134934.0001), Heuertz et al. (2006) identified heterozygosity for a de novo … (more)
In a boy with achondroplasia (100800) who was negative for the common G380R mutation (134934.0001), Heuertz et al. (2006) identified heterozygosity for a de novo 835A-C transversion in exon 7 of the FGFR3 gene, resulting in an ser279-to-cys (S279C) substitution in the IgIIIa extracellular domain. In addition to the typical skeletal features of ACH, the child had epilepsy and moderate learning difficulties. Severe kyphoscoliosis required surgical correction at age 7 years, which was complicated by postoperative lower limb paralysis requiring decompressive surgery. Friez and Wilson (2008) identified the S279C mutation in a newborn originally diagnosed with achondroplasia whose phenotype evolved into a milder form of hypochondroplasia (146000) in early childhood. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel FGFR3 mutations in exon 7 and implications for expanded screening of achondroplasia and hypochondroplasia: a response to Heuertz et al. | Friez MJ | European journal of human genetics : EJHG | 2008 | PMID: 17895900 |
Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. | Heuertz S | European journal of human genetics : EJHG | 2006 | PMID: 16912704 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3 | - | - | - | - |
Text-mined citations for rs121913114 ...
HelpRecord last updated Feb 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.