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

dbSNP: rs28933068

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255928	SCV000321638	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant results in significantly reduced expression patterns and reduced STAT1 phosphorylation (Raffioni et al., 1998; Krejci et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22045636, 19088846, 23165795, 19449430, 23614116, 16575888, 9452043, 9857065, 25614871, 10360393, 24630288, 23573386, 24715719, 25505998, 16222682, 16020314, 8589686, 30335613, 30138938, 29620724, 30355600, 31130284, 33942288, 30755392, 32964447, 20301650, 34006472, 33726816, 7670477)
Eurofins Ntd Llc (ga)	RCV000255928	SCV000337275	pathogenic	not provided	2018-06-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255928	SCV000603707	pathogenic	not 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	RCV000255928	SCV000640361	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sporadic or familial hypochondroplasia (PMID: 7670477, 8589686, 9452043, 11055896, 23165795, 25614871). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1659C>A. ClinVar contains an entry for this variant (Variation ID: 16337). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255928	SCV001247234	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255928	SCV001449694	pathogenic	not provided	2017-08-02	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000255928	SCV001832496	pathogenic	not provided	2020-01-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255928	SCV002023066	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
DASA	RCV000353403	SCV002061177	pathogenic	Achondroplasia	2022-01-05	criteria provided, single submitter	clinical testing	The c.1620C>A;p.(Asn540Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 16337; PMID: 23573386; 7670477; 8589686; 25614871) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11055896) - PS3_supporting.Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(ClinVar: 16338; PMID 23165795; 25614871) - PS1. This variant is not present in population databases (rs28933068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 16349; 16344) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000017740	SCV002507178	pathogenic	Hypochondroplasia	2022-05-09	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000017740	SCV002512718	pathogenic	Hypochondroplasia	2021-12-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273932	SCV002559082	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000255928	SCV002818216	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
3billion	RCV000017740	SCV003841359	pathogenic	Hypochondroplasia	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016337). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016344, VCV000016349, VCV000374828, VCV001325830). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000353403	SCV003915593	pathogenic	Achondroplasia	2021-05-21	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000017740	SCV004099083	pathogenic	Hypochondroplasia	2023-08-29	criteria provided, single submitter	clinical testing	PS2, PS4, PM1, PM2, PM3, PP3
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000353403	SCV004123066	pathogenic	Achondroplasia	2023-07-01	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000017740	SCV004244354	pathogenic	Hypochondroplasia	2024-01-22	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5_STR,PS1,PS3_MOD,PM2_SUP,PP3,PM1_SUP
PreventionGenetics, part of Exact Sciences	RCV003944827	SCV004757745	pathogenic	FGFR3-related condition	2023-11-09	criteria provided, single submitter	clinical testing	The FGFR3 c.1620C>A variant is predicted to result in the amino acid substitution p.Asn540Lys. This variant is reported to be the most common cause of hypochondroplasia (for example see: Bellus et al. 1995. PubMed ID: 7670477; Linnankivi et al. 2012. PubMed ID: 23165795; Mustafa et al. 2014. PubMed ID: 25505998; Xue et al. 2014. PubMed ID: 25614871; Maddirevula et al. 2018. PubMed ID: 29620724). This variant has been reported in the homozygous state in a patient with severe hypochondroplasia (De Rosa et al. 2014. PubMed ID: 24715719), and has also been reported in patients with thanatophoric dysplasia as part of a complex double de novo FGFR3 allele (Pannier et al. 2009. PubMed ID: 19449430; Marquis-Nicholson et al. 2013. PubMed ID: 23573386). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000017740	SCV000038018	pathogenic	Hypochondroplasia	1999-06-11	no assertion criteria provided	literature only
GeneReviews	RCV000017740	SCV000086721	not provided	Hypochondroplasia		no assertion provided	literature only	Most common pathogenic variant in hypochondroplasia
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255928	SCV001951990	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255928	SCV001966141	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000255928	SCV002036138	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000353403	SCV003927949	pathogenic	Achondroplasia	2023-04-01	no assertion criteria provided	clinical testing