VCV000441277.3 - ClinVar

NM_000142.4(FGFR3):c.[1454A>G;1620C>A]

Germline

Classification

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This haplotype includes the following variants

NM_000142.4(FGFR3):c.[1454A>G;1620C>A]

Other names: FGFR3, ASN540LYS AND GLN485ARG
Functional consequence: -
Links: ClinGen: CA357258; OMIM: 134934.0034

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
Gene	OMIM	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.
Thanatophoric dysplasia type 1	Pathogenic (1)	no assertion criteria provided	Jun 1, 2009	RCV000017771.34

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.
Pathogenic (Jun 01, 2009)	no assertion criteria provided Method: literature only	THANATOPHORIC DYSPLASIA, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038050.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 19449430 Comment on evidence: In a fetus with lethal thanatophoric dysplasia I (TD1; 187600), Pannier et al. (2009) identified 2 de novo heterozygous mutations in the FGFR3 gene on … (more) In a fetus with lethal thanatophoric dysplasia I (TD1; 187600), Pannier et al. (2009) identified 2 de novo heterozygous mutations in the FGFR3 gene on the same allele: N540K (134934.0010), and a 1454A-G transition, resulting in a gln485-to-arg (Q485R) substitution at a conserved residue in the beta-2 strand in the kinase domain. Protein modeling suggested that the mutations altered the receptor structure, holding it in a fully activated state, consistent with a gain of function. The pregnancy was terminated at 24 weeks' gestation after the fetus was noted to have severe dwarfism. Radiographic studies showed severe rhizomelic shortness of the long bones and mild bowing of the femora, radii, and ulnae. The spine showed severe platyspondyly with H-shaped vertebrae and narrowing of the interpediculate distance. The thorax was small with short ribs, and the iliac bones were short and wide. Macrocrania and frontal bossing were observed; there was no evidence of a cloverleaf skull. Postmortem examination showed cerebral cortical malformations and severe disorganization of growth plates in the long bones. The N540K mutation in isolation usually results in the less severe phenotype of hypochondroplasia (HCH; 146000). (less)

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

Title	Author	Journal	Year	Link
Hypochondroplasia.	Adam MP	-	2020	PMID: 20301650
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.	Monies D	American journal of human genetics	2019	PMID: 31130284
Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.	Maher GJ	Genome research	2018	PMID: 30355600
Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study.	Huang Z	Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology	2018	PMID: 30138938
Expanding the phenome and variome of skeletal dysplasia.	Maddirevula S	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29620724
FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.	Xue Y	Molecular genetics & genomic medicine	2014	PMID: 25614871
Molecular Analysis of a Case of Thanatophoric Dysplasia Reveals Two de novo FGFR3 Missense Mutations located in cis.	Marquis-Nicholson R	Sultan Qaboos University medical journal	2013	PMID: 23573386
Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation.	Linnankivi T	American journal of medical genetics. Part A	2012	PMID: 23165795
PTEN hamartoma tumor syndrome and Gorham-Stout phenomenon.	Hopman SM	American journal of medical genetics. Part A	2012	PMID: 22628360
Thanatophoric dysplasia caused by double missense FGFR3 mutations.	Pannier S	American journal of medical genetics. Part A	2009	PMID: 19449430
Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers.	Lachlan KL	Journal of medical genetics	2007	PMID: 17526800
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
Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome.	Chitayat D	American journal of medical genetics	1999	PMID: 10360393
Achondroplasia-hypochondroplasia complex in a newborn infant.	Huggins MJ	American journal of medical genetics	1999	PMID: 10360392
Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association.	Angle B	Clinical genetics	1998	PMID: 9842995
Genotype and phenotype in hypochondroplasia.	Ramaswami U	The Journal of pediatrics	1998	PMID: 9672519
Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia.	Deutz-Terlouw PP	Human mutation	1998	PMID: 9452043
Comparison of clinical-radiological and molecular findings in hypochondroplasia.	Prinster C	American journal of medical genetics	1998	PMID: 9450868
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
Observations suggesting allelism of the achondroplasia and hypochondroplasia genes.	McKusick VA	Journal of medical genetics	1973	PMID: 4697848
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3	-	-	-	-
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Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000142.4(FGFR3):c.[1454A>G;1620C>A]

Variant Details

NM_000142.4(FGFR3):c.[1454A>G;1620C>A]

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...