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

dbSNP: rs28931615

Total submissions: 15

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414319	SCV000762843	pathogenic	not provided	2024-11-03	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). Invitae Evidence 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 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	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017726	SCV005398656	pathogenic	Crouzon syndrome-acanthosis nigricans syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both gain and loss of function are known mechanisms of disease in this gene. Gain of function variants in this gene have been associated with autosomal dominant skeletal dysplasias, while loss of function variants have been associated with autosomal recessive CATSHL syndrome (PMID: 25614871). The disease mechanism for autosomal dominant LADD syndrome is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD syndrome patients, even within the same family (PMID: 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with craniosynostosis, Crouzon syndrome with acathosis nigricans and one de novo individual with Pfeiffer syndrome type 3 (ClinVar, LOVD, PMID: 31016899). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000017726	SCV000038004	pathogenic	Crouzon syndrome-acanthosis nigricans syndrome	2007-11-01	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