ClinVar Miner

Submissions for variant NM_000142.4(FGFR3):c.1620C>A (p.Asn540Lys) (rs28933068)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506429 SCV000603707 pathogenic not specified 2016-09-22 criteria provided, single submitter clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000017740 SCV000863901 pathogenic Hypochondroplasia 2018-06-18 no assertion criteria provided clinical testing
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255928 SCV000337275 pathogenic not provided 2018-06-02 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000017740 SCV000086721 pathologic Hypochondroplasia 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000528114 SCV000640361 pathogenic Craniosynostosis 2018-12-12 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.
OMIM RCV000017740 SCV000038018 pathogenic Hypochondroplasia 1999-06-11 no assertion criteria provided literature only

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