ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys) (rs28933068)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia,Universidade Católica de Brasília RCV000017741 SCV000223910 pathogenic Hypochondroplasia 2015-04-01 criteria provided, single submitter research
GeneDx RCV000255372 SCV000321637 pathogenic not provided 2017-05-17 criteria provided, single submitter clinical testing The N540K pathogenic variant in the FGFR3 gene has been reported previously in multiple individuals with hypochondroplasia (Prinos et al., 1995; Foldynova-Trantirkova et al., 2012). The N540K variant occurs in a tyrosine kinase domain of FGFR3 and functional studies indicate this variant results in significantly reduced expression patterns (Raffioni et al., 1998). The N540K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is well conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N540K as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255372 SCV000341534 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415460 SCV000492852 pathogenic Short stature 2015-06-23 criteria provided, single submitter clinical testing
Invitae RCV000540209 SCV000640362 pathogenic Craniosynostosis syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 540 of the FGFR3 protein (p.Asn540Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant is one of the most commonly reported causes of hypochondroplasia and has also been reported in individuals affected with achondroplasia (PMID: 23149434, 11754059, 8589686, 23165795, 25614871, 10360392). A different variant (c.1620C>A) giving rise to the same protein effect observed here (p.Asn540Lys) is also commonly reported in individuals affected with hypochondroplasia, and together these variants account for ~70% of all cases (PMID: 11055896, 23165795, 25614871, 7670477, 8589686, 9452043). This variant is also known as 1659C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 16338). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000622950 SCV000741814 pathogenic Inborn genetic diseases 2016-09-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255372 SCV000885457 pathogenic not provided 2017-11-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763122 SCV000893667 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
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255372 SCV001449926 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255372 SCV001500775 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001332222 SCV001524466 pathogenic Achondroplasia 2020-02-14 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Blueprint Genetics RCV000255372 SCV001832469 pathogenic not provided 2019-11-30 criteria provided, single submitter clinical testing
OMIM RCV000017741 SCV000038019 pathogenic Hypochondroplasia 1999-04-01 no assertion criteria provided literature only
GeneReviews RCV000017741 SCV000086722 pathologic Hypochondroplasia 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000017741 SCV000692270 pathogenic Hypochondroplasia 2016-04-06 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000017741 SCV000746072 pathogenic Hypochondroplasia 2017-09-18 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000255372 SCV001955913 pathogenic not provided no assertion criteria provided clinical testing

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