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

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255928	SCV000321638	pathogenic	not provided	2018-07-19	criteria provided, single submitter	clinical testing	The N540K pathogenic variant in the FGFR3 gene has been reported previously in the heterozygous state in multiple individuals with hypochondroplasia, as well as achondroplasia (Bellus et al., 1995; Xue et al., 2014). The N540K variant occurs in a tyrosine kinase domain of FGFR3 and functional studies show that this variant results in significantly reduced expression patterns and reduced STAT1 phosphorylation (Raffioni et al., 1998; Krejci et al., 2008). The N540K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The N540K variant is not observed in large population cohorts (Lek et al., 2016). We interpret N540K as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000255928	SCV000337275	pathogenic	not provided	2018-06-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000506429	SCV000603707	pathogenic	none provided	2019-11-03	criteria provided, single submitter	clinical testing	The FGFR3 c.1620C>A; p.Asn540Lys variant (rs28933068; ClinVarID: 16337) is reported in the literature in multiple individuals affected with hypochondroplasia and achondroplasia (Bellus 1995, Deutz-Terlouw 1998, Xue 2014). Together with another variant resulting in the same amino acid change (c.1620C>G; p.Asn540Lys), these account for over 50% of all hypochondroplasia cases (Bellus 2000, Linnankivi 2012, Xue 2014). The asparagine at codon 540 is highly conserved, and functional analyses of the variant protein show significant reductions in protein expression and kinase activity (Krejci 2008, Raffioni 1998). Based on available information, this variant is considered to be pathogenic. References: Bellus GA et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995 Jul;10(3):357-9. Bellus GA et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000 Dec;67(6):1411-21. Deutz-Terlouw PP et al. Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia. Hum Mutat. 1998;Suppl 1:S62-5. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008;3(12):e3961. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012 Dec;158A(12):3119-25. Raffioni S et al. Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation. J Biol Chem. 1998 Dec 25;273(52):35250-9. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014 Nov;2(6):497-503.
Invitae	RCV000528114	SCV000640361	pathogenic	Craniosynostosis syndrome	2020-01-02	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 (rs28933068, ExAC no frequency). This variant is one of the most commonly reported causes of sporadic or familial hypochondroplasia (PMID: 7670477, 8589686, 9452043, 25614871). A different variant (c.1620C>G) 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 50 to 76% of all cases (PMID: 11055896, 23165795, 25614871). This variant is also known as c.1659C>A in the literature. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000255928	SCV001247234	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000255928	SCV001449694	pathogenic	not provided	2017-08-02	criteria provided, single submitter	clinical testing
OMIM	RCV000017740	SCV000038018	pathogenic	Hypochondroplasia	1999-06-11	no assertion criteria provided	literature only
GeneReviews	RCV000017740	SCV000086721	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	RCV000017740	SCV000109626	pathogenic	Hypochondroplasia	2015-07-21	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000353403	SCV000692269	pathogenic	Achondroplasia	2015-07-21	no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare	RCV000017740	SCV000863901	pathogenic	Hypochondroplasia	2018-06-18	no assertion criteria provided	clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000017740	SCV001482319	pathogenic	Hypochondroplasia	2019-05-31	no assertion criteria provided	research