ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1172C>A (p.Ala391Glu)

dbSNP: rs28931615
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194803 SCV000247374 pathogenic Craniosynostosis syndrome 2015-07-27 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000017726 SCV000328409 pathogenic Crouzon syndrome-acanthosis nigricans syndrome 2016-10-20 criteria provided, single submitter clinical testing
GeneDx RCV000414319 SCV000491018 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing Published functional studies demonstrate a lower expression of the protein in comparison to wild-type and an increase in the phosphorylation level (Chen et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23727984, 9857065, 18976668, 23437153, 21536014, 27228464, 17935505, 27181494, 29620724, 8880573, 31016899, 31837199, 10670894, 7493034, 11426459, 20199409)
Ambry Genetics RCV000623005 SCV000741461 pathogenic Inborn genetic diseases 2016-04-18 criteria provided, single submitter clinical testing
Invitae RCV000414319 SCV000762843 pathogenic not provided 2023-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 391 of the FGFR3 protein (p.Ala391Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Crouzon syndrome with acanthosis nigricans (CSAN) (PMID: 7493034, 8880573, 11426459, 20199409). ClinVar contains an entry for this variant (Variation ID: 16329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 18976668, 21536014, 23437153). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000017726 SCV000807312 pathogenic Crouzon syndrome-acanthosis nigricans syndrome 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
Department of Medical Genetics, Oslo University Hospital RCV000017726 SCV001437560 pathogenic Crouzon syndrome-acanthosis nigricans syndrome criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000414319 SCV002023068 pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV000414319 SCV002525631 pathogenic not provided criteria provided, single submitter clinical testing The c.1172C>A variant, located in exon 9 of FGFR3, results in a substitution of alanine with glutamic acid at position 391 of the protein. This is a recurrent pathogenic variant that has previously been reported in several individuals with Crouzon syndrome with acanthosis nigricans (PMID: 7493034, 8880573, 17935505, 31016899, NBK1455). In these reports, common clinical features include craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia or stenosis, hydrocephalus, and acanthosis nigricans. Other features such as Chiari malformations, vertebral anomalies, and subtle skeletal findings have also been reported. This variant is absent from large population cohorts (0 of >281,000 alleles; Genome Aggregation Database v2.1). The Ala391Glu change has been experimentally demonstrated to cause an increase in FGFR3 activation by means of FGFR3 dimer stabilization and phosphorylation of critical tyrosines in the FGFR3 activation loop (PMID: 23437153).
Institute of Human Genetics, University of Leipzig Medical Center RCV000017726 SCV004027639 pathogenic Crouzon syndrome-acanthosis nigricans syndrome 2023-07-10 criteria provided, single submitter clinical testing Criteria applied: PS2,PS4,PS3_MOD,PM2_SUP,PP3
OMIM RCV000017726 SCV000038004 pathogenic Crouzon syndrome-acanthosis nigricans syndrome 2007-11-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439126 SCV000510403 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000017726 SCV000692267 pathogenic Crouzon syndrome-acanthosis nigricans syndrome 2009-12-24 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000414319 SCV001807532 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000414319 SCV001971435 pathogenic not provided no assertion criteria provided clinical testing

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