Submissions for variant NM_000141.5(FGFR2):c.1052C>G (p.Ser351Cys)

dbSNP: rs121918502

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256107	SCV000322317	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Recurrent variant in the immunoglobulin-like domain 3, typically associated with a severe form of Pfeiffer syndrome (Lajeunie et al., 2006; Stevens et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8946174, 23754559, 16955501, 18391498, 34909104, 34367232, 30976282, 9714439, 10406670, 24127277, 23348274, 12544231, 20818252, 9605588, 15996217, 12072807, 16760743, 10633130, 29436723, 29280877, 29230096, 16465081, 9693549, 30355600, 31301044, 16418739, 31222448, 30976276, 32333414, 32732226, 34580403)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000415503	SCV000328398	pathogenic	Pfeiffer syndrome	2016-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528973	SCV000659607	pathogenic	FGFR2-related craniosynostosis	2023-09-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 13286). This missense change has been observed in individual(s) with severe forms of Crouzon or Pfeiffer syndromes (PMID: 8946174, 10406670, 16418739, 23348274, 24656465). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 351 of the FGFR2 protein (p.Ser351Cys).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000415503	SCV000803777	pathogenic	Pfeiffer syndrome	2015-07-30	criteria provided, single submitter	clinical testing
3billion	RCV003313920	SCV004013785	pathogenic	Crouzon syndrome		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 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: VCV000013286 / PMID: 8946174). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000014208	SCV000034456	pathogenic	Pfeiffer syndrome type 3	2005-08-01	no assertion criteria provided	literature only
OMIM	RCV000014209	SCV000034457	pathogenic	Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis	2005-08-01	no assertion criteria provided	literature only
Pediatric Genetics Clinic, Sheba Medical Center	RCV000014209	SCV001712177	pathogenic	Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis	2021-05-13	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000256107	SCV001952131	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256107	SCV001971068	pathogenic	not provided		no assertion criteria provided	clinical testing
Human Genetics Unit, University Of Colombo	RCV000415503	SCV002558846	pathogenic	Pfeiffer syndrome	2021-12-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737152	SCV005361514	pathogenic	FGFR2-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The FGFR2 c.1052C>G variant is predicted to result in the amino acid substitution p.Ser351Cys. This variant has been well documented to be pathogenic for Pfeiffer syndrome (Gripp et al. 1998. PubMed ID: 9714439; Chokdeemboon et al. 2013. PubMed ID: 23348274; Nur BG et al 2014. PubMed ID: 24656465). It was also found in patients with Antley-Bixler and Beare-Stevenson syndromes (Roscioli et al. 2013. PubMed ID: 24127277). Additionally, this variant was documented in the de novo state in a fetus with Apert syndrome (Table S2. Fu et al. 2022. PubMed ID: 36307859). This variant is interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/13286/). This variant has not been reported in gnomAD, indicating it is rare. Taken together, this variant is interpreted as pathogenic.