NM_000142.5(FGFR3):c.1948A>C (p.Lys650Gln) AND Hypochondroplasia

Clinical significance:Uncertain significance (Last evaluated: May 28, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000017757.35

Allele description [Variation Report for NM_000142.5(FGFR3):c.1948A>C (p.Lys650Gln)]

NM_000142.5(FGFR3):c.1948A>C (p.Lys650Gln)

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.1948A>C (p.Lys650Gln)
HGVS:
  • NC_000004.12:g.1806162A>C
  • NG_012632.1:g.17851A>C
  • NM_000142.5:c.1948A>CMANE SELECT
  • NM_001163213.1:c.1954A>C
  • NM_001163213.2:c.1954A>C
  • NM_001354809.2:c.1951A>C
  • NM_001354810.2:c.1951A>C
  • NM_022965.4:c.1612A>C
  • NP_000133.1:p.Lys650Gln
  • NP_000133.1:p.Lys650Gln
  • NP_001156685.1:p.Lys652Gln
  • NP_001156685.1:p.Lys652Gln
  • NP_001341738.1:p.Lys651Gln
  • NP_001341739.1:p.Lys651Gln
  • NP_075254.1:p.Lys538Gln
  • LRG_1021t1:c.1948A>C
  • LRG_1021t2:c.1954A>C
  • LRG_1021:g.17851A>C
  • LRG_1021p1:p.Lys650Gln
  • LRG_1021p2:p.Lys652Gln
  • NC_000004.11:g.1807889A>C
  • NM_000142.4:c.1948A>C
  • NR_148971.2:n.2374A>C
  • P22607:p.Lys650Gln
Note:
NCBI staff reviewed the sequence information reported in PubMed 11314002 Fig. 1C to determine the location of this allele on the current reference sequence.
Protein change:
K538Q; LYS650GLN
Links:
UniProtKB: P22607#VAR_018390; OMIM: 134934.0022; OMIM: 134934.0024; dbSNP: rs78311289
NCBI 1000 Genomes Browser:
rs78311289
Molecular consequence:
  • NM_000142.5:c.1948A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001163213.1:c.1954A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001163213.2:c.1954A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354809.2:c.1951A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354810.2:c.1951A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022965.4:c.1612A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148971.2:n.2374A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hypochondroplasia (HCH)
Identifiers:
MONDO: MONDO:0007793; MedGen: C0410529; Orphanet: 429; OMIM: 146000

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000038035OMIMno assertion criteria providedPathogenic
(Dec 15, 2007)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000086723GeneReviewsno assertion criteria providedpathologic
(Sep 26, 2013)
not providedcuration

SCV000692268Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospitalno assertion criteria providedPathogenic
(Jan 23, 2015)
germlineclinical testing

SCV001136685Mendelicscriteria provided, single submitter
Uncertain significance
(May 28, 2019)
unknownclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.

Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA.

Am J Hum Genet. 2000 Dec;67(6):1411-21. Epub 2000 Oct 27.

PubMed [citation]
PMID:
11055896
PMCID:
PMC1287918

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia.

Heuertz S, Le Merrer M, Zabel B, Wright M, Legeai-Mallet L, Cormier-Daire V, Gibbs L, Bonaventure J.

Eur J Hum Genet. 2006 Dec;14(12):1240-7. Epub 2006 Aug 16. Erratum in: Eur J Hum Genet. 2006 Dec;14(12):1321.

PubMed [citation]
PMID:
16912704
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000038035.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

Bellus et al. (2000) identified a 1948A-C transversion in the FGFR3 gene, predicting a lys650-to-gln (K650Q) amino acid substitution and causing hypochondroplasia (146000) in a form milder than that seen in individuals with the asn540-to-lys (134934.0010) or lys650-to-met (134934.0015) mutations.

Heuertz et al. (2006) identified the K560Q mutation in a patient with a moderate form of hypochondroplasia.

Leroy et al. (2007) identified the K650Q mutation in a patient with a mild form of hypochondroplasia who was also diagnosed with acanthosis nigricans at 8 years of age. Leroy et al. (2007) stated that the mutation is located in the second part (3-prime side) of the split tyrosine kinase domain in the intracellular portion of the single-pass transmembrane of the receptor and that it unfavorably modulates the receptor's physiologic downstream inhibitory signaling.

Sibley et al. (2001) found the same mutation, which they designated LYS652GLN (K652Q), in a transitional cell carcinoma of the bladder (109800).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000086723.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital, SCV000692268.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001136685.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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