NM_000142.4(FGFR3):c.1620C>A (p.Asn540Lys)

NM_000142.4(FGFR3):c.1620C>A (p.Asn540Lys)

Variant type:
single nucleotide variant
Cytogenetic location:
4p16
Genomic location:
  • Chr4:1805644 (on Assembly GRCh38)
  • Chr4:1807371 (on Assembly GRCh37)
Other names:
  • FGFR3, ASN540LYS, 1620C-A
Protein change:
N540K
HGVS:
  • NG_012632.1:g.17333C>A
  • NM_000142.4:c.1620C>A
  • NC_000004.12:g.1805644C>A (GRCh38)
  • NP_000133.1:p.Asn540Lys
  • NC_000004.11:g.1807371C>A (GRCh37)
  • NM_000142.4:c.1620C>A(C1659A)
Links:
NCBI 1000 Genomes Browser:
rs28933068
Molecular consequence:
NM_000142.4:c.1620C>A: missense variant [Sequence Ontology SO:0001583]

Clinical significance

NM_000142.4(FGFR3):c.1620C>A (p.Asn540Lys)

Clinical significance:
Pathogenic
Review status:
2 stars out of maximum of 4 stars
classified by multiple submitters
Number of submission(s):
2
Condition(s)
See supporting ClinVar records

Assertions for related alleles

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

Clinical significance:
Pathogenic
Review status:
1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
1
Condition(s)
See supporting ClinVar records

Browser views

Recent activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter - Study name
(Last submitted)
Submission accession
Pathogenic
(Apr 1, 2013)
classified by single submitter
(literature only)
literature onlygermlinePubMed (8)
[See all records that cite these PMIDs]
OMIM

(Dec 30, 2010)

SCV000038018
Pathogenic
(Sep 26, 2013)
classified by single submitter
(literature only)
literature onlynot providedPubMed (1)
[See all records that cite this PMID]
GeneReviews

(Apr 30, 2013)

SCV000086721

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermline, not providednot providednot provided

GeneReviews

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

Among 65 patients with hypochondroplasia, Ramaswami et al. (1998) found that 28 (43%) were heterozygous for the 1620C-A transversion resulting in the asn540-to-lys amino acid substitution in the tyrosine kinase domain of FGFR3.
Angle et al. (1998) found the 1620C-A mutation in FGFR3 in a patient with hypochondroplasia associated with cloverleaf skull deformity. Cloverleaf skull had not previously been reported in hypochondroplasia.
Bellus et al. (1995) referred to the nucleotide as 1620; Prinos et al. (1995) referred to the nucleotide as 1659. Both groups numbered the amino acid as 540.
Huggins et al. (1999) reported an 8-month-old girl with achondroplasia/hypochondroplasia whose father had the G380R mutation and whose mother had the N450K mutation. Chitayat et al. (1999) simultaneously reported an infant boy with achondroplasia/hypochondroplasia whose mother had the G380R mutation and whose father had the N450K mutation. Molecular analysis confirmed the compound heterozygosity of both children, who displayed an intermediate phenotype that was more severe than either condition in the heterozygous state but less severe than homozygous ACH.
In 8 of 14 unrelated patients with hypochondroplasia (146000), Bellus et al. (1995) found a C-to-A transversion at nucleotide 1620 of the FGFR3 gene, resulting in an asn540-to-lys (N540K) substitution in the proximal tyrosine kinase domain of the protein. This mutation was demonstrated in the severely affected woman thought to represent a hypochondroplasia/achondroplasia compound heterozygote (McKusick et al., 1973); the other allele carried the common achondroplasia mutation: gly380 to arg (134934.0001). Prinos et al. (1995) found the same mutation in 4 cases and confirmed its occurrence in the hypochondroplasia/achondroplasia compound heterozygote.
Prinster et al. (1998) selected 18 patients with a phenotype compatible with hypochondroplasia based on the most common radiologic criteria. The presence of the N540K mutation was verified by restriction enzyme digestions in 9 of the 18 patients. Although similar in phenotype to patients without the mutation, these 9 had the additional feature of relative macrocephaly. Furthermore, the association of the unchanged or narrow interpedicular distance with the fibula longer than the tibia was more common in patients with the N540K mutation.

Last Updated: May 21, 2015