NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys) AND not provided

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255372.53

Allele description [Variation Report for NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)]

NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)

Gene:

FGFR3:fibroblast growth factor receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)

Other names:

FGFR3, ASN540LYS, 1620C-G

HGVS:

NC_000004.12:g.1805644C>G
NG_012632.1:g.17333C>G
NM_000142.5:c.1620C>GMANE SELECT
NM_001163213.2:c.1626C>G
NM_001354809.2:c.1623C>G
NM_001354810.2:c.1623C>G
NM_022965.4:c.1284C>G
NP_000133.1:p.Asn540Lys
NP_000133.1:p.Asn540Lys
NP_001156685.1:p.Asn542Lys
NP_001156685.1:p.Asn542Lys
NP_001341738.1:p.Asn541Lys
NP_001341739.1:p.Asn541Lys
NP_075254.1:p.Asn428Lys
LRG_1021t1:c.1620C>G
LRG_1021t2:c.1626C>G
LRG_1021:g.17333C>G
LRG_1021p1:p.Asn540Lys
LRG_1021p2:p.Asn542Lys
NC_000004.11:g.1807371C>G
NM_000142.2:c.1620C>G
NM_000142.4:c.1620C>G
NM_001163213.1:c.1626C>G
NR_148971.2:n.2046C>G

Protein change:

N428K; ASN540LYS

Links:

OMIM: 134934.0012; dbSNP: rs28933068

NCBI 1000 Genomes Browser:

rs28933068

Molecular consequence:

NM_000142.5:c.1620C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001163213.2:c.1626C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354809.2:c.1623C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354810.2:c.1623C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_022965.4:c.1284C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148971.2:n.2046C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321637	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 17, 2022)	germline	clinical testing	Citation Link,
SCV000341534	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Apr 5, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23149434, 25614871, 8589686 Citation Link,
SCV000640362	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 7670477, 8589686, 9452043, 10360392, 11055896, 11754059, 23149434, 23165795, 25614871, 19088846, 28492532
SCV000885457	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 18, 2023)	germline	clinical testing	Citation Link,
SCV001449926	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001500775	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2022)	germline	clinical testing	Citation Link,
SCV001832469	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Nov 30, 2019)	germline	clinical testing	Citation Link,
SCV001955913	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001964698	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002036285	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.

Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA.

Nat Genet. 1995 Jul;10(3):357-9.

PubMed [citation]

PMID:: 7670477

A common FGFR3 gene mutation in hypochondroplasia.

Prinos P, Costa T, Sommer A, Kilpatrick MW, Tsipouras P.

Hum Mol Genet. 1995 Nov;4(11):2097-101.

PubMed [citation]

PMID:: 8589686

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000321637.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in multiple individuals with hypochondroplasia in the published literature (Prinos et al., 1995; Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate this variant results in significantly reduced in vitro expression (Raffioni et al., 1998); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8640234, 29681095, 10360392, 22045636, 23149434, 9857065, 23165795, 11754059, 19088846, 8589686, 28777845, 29478821, 29150894, 17621485, 29620724, 30355600, 26380986, 34567078, 33942288, 32712949, 33389251)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000341534.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		4	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000640362.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypochondroplasia or achondroplasia (PMID: 7670477, 8589686, 9452043, 10360392, 11055896, 11754059, 23149434, 23165795, 25614871). ClinVar contains an entry for this variant (Variation ID: 16338). 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%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885457.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The FGFR3 c.1620C>G; p.Asn540Lys variant (rs28933068) is a recurrent alteration in patients with hypochondroplasia (Camera 2001, Kannu 2007, Korkmaz 2012, Linnankivi 2012, Xue 2014). Another variant at this position, c.1620C>A, also results in the same amino acid alteration (p.Asn540Lys), and is the most common pathogenic variant in hypochondroplasia patients (Xue 2014). Functional characterization of the variant protein indicates increased phosphorylation of ERK1/2, resulting in an over-activation of the MAPK signaling pathway (Krejci 2008). The c.1620C>G; p.Asn540Lys variant is reported in ClinVar (Variation ID: 16338). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, the p.Asn540Lys variant is considered to be pathogenic. References: Camera G et al. Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype. Am J Med Genet. 2001; 104(4):277-81. PMID: 11754059. Kannu P et al. FGFR3 mutations and medial temporal lobe dysgenesis. J Child Neurol. 2007; 22(2):211-3. PMID: 17621485. Korkmaz HA et al. Hypochondroplasia in a child with 1620C>G (Asn540Lys) mutation in FGFR3. J Clin Res Pediatr Endocrinol. 2012; 4(4):220-2. PMID: 23149434. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008; 3(12):e3961. PMID: 19088846. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012; 158A(12):3119-25. PMID: 23165795. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014; 2(6):497-503. PMID: 25614871.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449926.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001500775.23

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

FGFR3: PS4, PM2, PM6, PP3, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Blueprint Genetics, SCV001832469.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955913.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001964698.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036285.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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