ClinVar Genomic variation as it relates to human health
NM_000142.5(FGFR3):c.1619A>G (p.Asn540Ser)
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.
Pathogenic(7); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000142.5(FGFR3):c.1619A>G (p.Asn540Ser)
Variation ID: 16349 Accession: VCV000016349.20
- Type and length
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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
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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 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000142.5:c.1619A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000133.1:p.Asn540Ser missense NM_001163213.2:c.1625A>G NP_001156685.1:p.Asn542Ser missense NM_001354809.2:c.1622A>G NP_001341738.1:p.Asn541Ser missense NM_001354810.2:c.1622A>G NP_001341739.1:p.Asn541Ser missense NM_022965.4:c.1283A>G NP_075254.1:p.Asn428Ser missense NR_148971.2:n.2045A>G non-coding transcript variant NC_000004.12:g.1805643A>G NC_000004.11:g.1807370A>G NG_012632.1:g.17332A>G LRG_1021:g.17332A>G LRG_1021t1:c.1619A>G LRG_1021p1:p.Asn540Ser P22607:p.Asn540Ser - Protein change
- N540S, N542S, N541S, N428S
- Other names
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- Canonical SPDI
- NC_000004.12:1805642: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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 | ||
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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
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. |
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FGFR3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
934 | 1082 |
Conditions - Germline
Condition
Help
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
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Feb 23, 2023 | RCV000017758.31 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 25, 2016 | RCV000623459.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2023 | RCV001269614.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2022 | RCV002262566.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002273934.1 |
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
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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
(Mar 28, 2018)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449719.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Achondroplasia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Suma Genomics
Accession: SCV002543817.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental delay
Affected status: yes
Allele origin:
inherited
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559067.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
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Pathogenic
(Dec 28, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819863.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: FGFR3 c.1619A>G (p.Asn540Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: FGFR3 c.1619A>G (p.Asn540Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250598 control chromosomes. c.1619A>G has been reported in the literature in multiple families affected with Hypochondroplasia and shown to segregate with disease (deSanctis_2012, Mortier_2000, Thauvin-Robinet_2003). These data indicate that the variant is very likely to be associated with disease. Other variants at this amino acid, N540K and N540T have also been reported to associate with Hypochondroplasia in the literature. At least one publication reports experimental evidence evaluating an impact on protein function (Patani_2016). These results showed a 10 fold increase in auto-phosphorylation and a 2 fold increase in substrate phosphorylation. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and Pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 14, 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: SCV001774147.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29542187, 10777366, 23045425, 15909185, 12707965) (less)
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypochondroplasia
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841545.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016349). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Lys, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016337, VCV000016338, VCV000016344, VCV000374828, VCV001325830). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Short stature (present) , Rhizomelia (present) , Brachydactyly (present) , Broad hallux (present) , 2-3 toe syndactyly (present) , Wide mouth (present) , Thick vermilion … (more)
Short stature (present) , Rhizomelia (present) , Brachydactyly (present) , Broad hallux (present) , 2-3 toe syndactyly (present) , Wide mouth (present) , Thick vermilion border (present) , Low hanging columella (present) (less)
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Uncertain significance
(Apr 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741473.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Global developmental delay (present) , Triangular face (present) , Frontal bossing (present) , Abnormal hair whorl (present) , Hirsutism (present) , … (more)
Short stature (present) , Global developmental delay (present) , Triangular face (present) , Frontal bossing (present) , Abnormal hair whorl (present) , Hirsutism (present) , Upslanted palpebral fissure (present) , Long eyelashes (present) , Prominent nasal bridge (present) , Bulbous nose (present) , Broad columella (present) , Underdeveloped nasal alae (present) , Narrow mouth (present) , Thin vermilion border (present) , Long philtrum (present) , Dental crowding (present) , Retrognathia (present) , Prominent fingertip pads (present) , Medial flaring of the eyebrow (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Nov 14, 2023)
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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: SCV002507760.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the FGFR3 protein (p.Asn540Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the FGFR3 protein (p.Asn540Ser). This variant is present in population databases (rs77722678, gnomAD no frequency). This missense change has been observed in individuals with hypochondroplasia (PMID: 10777366, 12707965, 23045425). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16349). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. 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: 11055896, 23165795, 25614871). 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. (less)
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Pathogenic
(May 15, 2003)
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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: SCV000038036.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Mortier et al. (2000) reported a father and daughter with clinical and radiographic features of hypochondroplasia who were heterozygous for an A-to-G transition resulting in … (more)
Mortier et al. (2000) reported a father and daughter with clinical and radiographic features of hypochondroplasia who were heterozygous for an A-to-G transition resulting in the replacement of an asparagine residue at position 540 by a serine residue (N540S). Both individuals were mildly affected. The father's height was between the 3rd and 25th centile; he had short limbs and relative macrocephaly. Radiographs showed definite features of hypochondroplasia. The daughter was below the 3rd centile in height with short limbs, frontal bossing, and lumbar hyperlordosis. Radiographic features were subtle. Thauvin-Robinet et al. (2003) described a family in which the N540S mutation was present in 2 brothers and their father. The proband was a 2-month-old boy referred for assessment of short limbs and macrocephaly. His brother, age 2.5 years, showed a height within the normal limits but macrocephaly with frontal bossing and mild micromelia were evident. Family history indicated micromelia and macrocephaly in the paternal grandfather (height, 163 cm) and the father's sister. (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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Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use. | Patani H | Oncotarget | 2016 | PMID: 26992226 |
Fibroblast growth factor signaling in skeletal development and disease. | Ornitz DM | Genes & development | 2015 | PMID: 26220993 |
FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. | Xue Y | Molecular genetics & genomic medicine | 2014 | PMID: 25614871 |
ASN540SER mutation is associated with a mild form of hypochondroplasia: a 7 years follow-up in an Italian boy. | De Sanctis V | Georgian medical news | 2012 | PMID: 23045425 |
Hypochondroplasia and stature within normal limits: another family with an Asn540Ser mutation in the fibroblast growth factor receptor 3 gene. | Thauvin-Robinet C | American journal of medical genetics. Part A | 2003 | PMID: 12707965 |
Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. | Bellus GA | American journal of human genetics | 2000 | PMID: 11055896 |
Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene. | Mortier G | Journal of medical genetics | 2000 | PMID: 10777366 |
A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online. | Grigelioniené G | Human mutation | 1998 | PMID: 10215410 |
Text-mined citations for rs77722678 ...
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.