In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine.
ClinVar Genomic variation as it relates to human health
NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr)
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.
(6)
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
6
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.1619A>C (p.Asn540Thr)
Variation ID: 16344 Accession: VCV000016344.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1805643 (GRCh38) [ NCBI UCSC ] 4: 1807370 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 26, 2024 Dec 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000142.5:c.1619A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000133.1:p.Asn540Thr missense NM_001163213.2:c.1625A>C NP_001156685.1:p.Asn542Thr missense NM_001354809.2:c.1622A>C NP_001341738.1:p.Asn541Thr missense NM_001354810.2:c.1622A>C NP_001341739.1:p.Asn541Thr missense NM_022965.4:c.1283A>C NP_075254.1:p.Asn428Thr missense NR_148971.2:n.2045A>C non-coding transcript variant NC_000004.12:g.1805643A>C NC_000004.11:g.1807370A>C NG_012632.1:g.17332A>C LRG_1021:g.17332A>C LRG_1021t1:c.1619A>C LRG_1021p1:p.Asn540Thr P22607:p.Asn540Thr - Protein change
- N540T, N542T, N428T, N541T
- Other names
- -
- Canonical SPDI
- NC_000004.12:1805642:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
983 | 1133 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
- | RCV000017753.32 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV001549822.13 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002507644.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. (less)
|
|
|
Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001770044.4
First in ClinVar: Aug 07, 2021 Last updated: Jul 23, 2024 |
Comment:
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); … (more)
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: 25728633, 9452043, 30048571, 30681580, 35438268) (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Hypochondroplasia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV005375364.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037932.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
|
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Pathogenic
(Jan 01, 1998)
|
no assertion criteria provided
Method: literature only
|
HYPOCHONDROPLASIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038031.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In a family in which members were affected with hypochondroplasia (HCH; 146000) in 3 generations, Deutz-Terlouw et al. (1998) found an A-to-C transversion at nucleotide … (more)
In a family in which members were affected with hypochondroplasia (HCH; 146000) in 3 generations, Deutz-Terlouw et al. (1998) found an A-to-C transversion at nucleotide 1658 of the FGFR3 gene, predicted to result in an asn540-to-thr substitution. The index patient was a 35-year-old male with mild rhizomelic limb shortening, stocky build, mild frontal bossing, and some limitation of pronation and supination of the left elbow. His height was 160 cm, his span 155.5 cm, and his skull circumference 56 cm. Radiographic examination showed short femoral necks, generalized brachydactyly, and absence of normal widening of the spinal canal in the lumbar area. Clinical findings in 2 of his 3 children and in his mother were similar. One of the affected sons also showed learning disabilities. The clinical symptoms, including macrocephaly and lumbar hyperlordosis, were more pronounced in him than in the other affected family members. The same codon was involved as in the more common asn540-to-lys mutation (134934.0010). (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037525.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
Comment:
Comment:
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: 25728633, 9452043, 30048571, 30681580, 35438268)
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:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine.
Comment:
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: 25728633, 9452043, 30048571, 30681580, 35438268)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. | Xue Y | Molecular genetics & genomic medicine | 2014 | PMID: 25614871 |
| Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia. | Deutz-Terlouw PP | Human mutation | 1998 | PMID: 9452043 |
| A common FGFR3 gene mutation in hypochondroplasia. | Prinos P | Human molecular genetics | 1995 | PMID: 8589686 |
| A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. | Bellus GA | Nature genetics | 1995 | PMID: 7670477 |
Text-mined citations for rs77722678 ...
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 27, 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.