ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1949A>C (p.Lys650Thr) (rs121913105)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542319 SCV000640368 pathogenic Craniosynostosis syndrome 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 650 of the FGFR3 protein (p.Lys650Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (rs121913105, ExAC no frequency). This variant has been reported to segregate with disease in multiple families affected with acanthosis nigricans (PMID: 17875876, 26818779, 25809207). It has also been shown to segregate with disease in a large family affected with hypochondroplasia and acanthosis nigricans (PMID: 18583390). Experimental studies have shown that this missense change causes constitutive tyrosine kinase activation (PMID: 11055896). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763123 SCV000893668 pathogenic Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cancer of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Urinary bladder cancer; Hypochondroplasia; Epidermal nevus; Severe achondroplasia with developmental delay and acanthosis nigricans; Malignant tumor of testis; Carcinoma of colon 2018-10-31 criteria provided, single submitter clinical testing
Breda Genetics srl RCV001254893 SCV001371842 pathogenic FGFR3-related disorder 2020-03-23 criteria provided, single submitter clinical testing The variant c.1955A>C (p.Lys652Thr), also known as p.Lys650Thr, is reported as pathogenic for FGFR3 related disorders in ClinVar (Variation ID: 65855) There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 3.12). The variant has been firstly reported by Berk et al. in a familial case of acanthosis nigricans associated with slightly short stature, without other anomalies (Berk et al., 2007, PMID: 17875876). Later, the same mutation has been described in a familial case of hypochondroplasia (HCH) and acanthosis nigricans (AN) by Castro-Feijo´o et al. (2008). Cossiez Cacard et al. (2016) found this mutation in a family with AN associated with hypochondroplasia. Codon 650 of FGFR3 is located in the tyrosine kinase domain II. Mutations of this codon have been reported in skeletal disorders including hypochondroplasia (p.Lys650Asn and p.Lys650Gln), SADDAN syndrome (p.Lys650Met), thanatophoric dysplasia type I (p.Lys650Met), and thanatophoric dysplasia type II (p.Lys650Glu) (Berk et al., 2007, PMID: 17875876).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001543530 SCV001762154 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
GeneReviews RCV000056100 SCV000087172 pathologic Hypochondroplasia 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.

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