ClinVar Miner

Submissions for variant NM_000142.4(FGFR3):c.1172C>A (p.Ala391Glu) (rs28931615)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623005 SCV000741461 pathogenic Inborn genetic diseases 2016-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Miraca Genetics Laboratories, RCV000017726 SCV000807312 pathogenic Crouzon syndrome with acanthosis nigricans 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 2-year-old female with Crouzon syndrome
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000017726 SCV000692267 pathogenic Crouzon syndrome with acanthosis nigricans 2009-12-24 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000439126 SCV000510403 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017726 SCV000328409 pathogenic Crouzon syndrome with acanthosis nigricans 2016-10-20 criteria provided, single submitter clinical testing
GeneDx RCV000414319 SCV000491018 pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing The A391E pathogenic variant in the FGFR3 gene has been reported previously in multiple individuals with craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and acanthosis nigricans (Meyers et al., 1995; Schweitzer et al., 2001; Sharda et al., 2010). Functional studies demonstrate that A391E causes an increase in FGFR3 phosphorylation and enhanced ligand-independent FGFR3 activation, resulting in dimer over-stabilization (Chen et al., 2011). The A391E variant is not observed in large population cohorts (Lek et al., 2016). The A391E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret A391E as a pathogenic variant,
Genetic Services Laboratory, University of Chicago RCV000194803 SCV000247374 pathogenic Craniosynostosis 2015-07-27 criteria provided, single submitter clinical testing
Invitae RCV000194803 SCV000762843 pathogenic Craniosynostosis 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 391 of the FGFR3 protein (p.Ala391Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Crouzon syndrome and acanthosis nigricans (CSAN) (PMID: 7493034, 8880573, 11426459, 20199409). ClinVar contains an entry for this variant (Variation ID: 16329). Experimental studies have shown that this missense change increases FGFR3 dimerization, facilitates the phosphorylation of critical tyrosine residues in the activation loop of FGFR3, and results in substantially increased FGFR3 activity (PMID: 18976668, 21536014, 23437153). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017726 SCV000038004 pathogenic Crouzon syndrome with acanthosis nigricans 2007-11-01 no assertion criteria provided literature only

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