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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 8, 2025
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:: RCV001332222.18

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

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)

Name:: Achondroplasia (ACH)
Synonyms:: Achondroplastic dwarfism
Identifiers:: MONDO: MONDO:0007037; MedGen: C0001080; Orphanet: 15; OMIM: 100800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001524466	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572640	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10777366, 8589686, 25614871, 25741868
SCV002581158	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005381294	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 7, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29620724, 35726512 Citation Link,
SCV005417699	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Nuytinck L, Craen M, Renard JP, Leroy JG, de Paepe A.

J Med Genet. 2000 Mar;37(3):220-4. No abstract available.

PubMed [citation]

PMID:: 10777366
PMCID:: PMC1734544

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 (6)

Details of each submission

From Baylor Genetics, SCV001524466.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From 3billion, SCV002572640.5

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

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016338 /PMID: 8589686 /3billion dataset). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016344, VCV000016349, VCV000374828, VCV001325830 /PMID: 10777366, 39498320, 9452043 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	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 MGZ Medical Genetics Center, SCV002581158.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005381294.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: FGFR3 c.1620C>G (p.Asn540Lys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250610 control chromosomes (gnomAD). c.1620C>G has been reported in the literature in multiple individuals affected with Hypochondroplasia, in some cases as a de novo occurrence (e.g. Maddirevula_2018, Zhu_2022). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1619A>G, p.Asn540Ser), supporting the critical relevance of codon 540 to FGFR3 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 29620724, 35726512). ClinVar contains an entry for this variant (Variation ID: 16338). Based on the evidence outlined above, the variant was 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 Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005417699.4

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

Description

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

#	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: Jul 6, 2026

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