Submissions for variant NM_000141.5(FGFR2):c.1124A>G (p.Tyr375Cys)

dbSNP: rs121913478

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224124	SCV000280700	pathogenic	not provided	2014-08-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000224124	SCV000322316	pathogenic	not provided	2023-03-26	criteria provided, single submitter	clinical testing	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: 12000365, 12900900, 23754559, 16531735, 25937001, 17525745, 19610084, 12145519, 27079505, 21397175, 17449949, 35050789, 32158469, 21479481, 8696350, 9545103, 25706251, 20856019)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000014198	SCV000328400	pathogenic	Beare-Stevenson cutis gyrata syndrome	2016-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549100	SCV000659609	pathogenic	FGFR2-related craniosynostosis	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the FGFR2 protein (p.Tyr375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Beare-Stevenson cutis gyrata syndrome (PMID: 8696350, 12145519, 12900900, 16531735, 20856019, 21397175, 25706251, 25937001, 27079505). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13277). 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) indicates that this missense variant is not expected to disrupt FGFR2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762799	SCV000893149	pathogenic	Acrocephalosyndactyly type I; Beare-Stevenson cutis gyrata syndrome; Jackson-Weiss syndrome; Levy-Hollister syndrome; Pfeiffer syndrome; Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; Crouzon syndrome; Saethre-Chotzen syndrome; Familial scaphocephaly syndrome, McGillivray type; Neoplasm of stomach; Bent bone dysplasia syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000014198	SCV001437559	likely pathogenic	Beare-Stevenson cutis gyrata syndrome		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000224124	SCV001447767	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology	RCV000014198	SCV001809945	pathogenic	Beare-Stevenson cutis gyrata syndrome		criteria provided, single submitter	clinical testing	Recurrent pathogenic: RCV000762799
Baylor Genetics	RCV000014198	SCV005049673	pathogenic	Beare-Stevenson cutis gyrata syndrome	2024-01-09	criteria provided, single submitter	clinical testing
OMIM	RCV000014198	SCV000034446	pathogenic	Beare-Stevenson cutis gyrata syndrome	2007-11-01	no assertion criteria provided	literature only
OMIM	RCV000014199	SCV000034447	pathogenic	Endometrial carcinoma	2007-11-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532336	SCV004727402	pathogenic	FGFR2-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The FGFR2 c.1124A>G variant is predicted to result in the amino acid substitution p.Tyr375Cys. This variant has been well documented to be pathogenic for Beare-Stevenson cutis gyrata syndrome (see for example Przylepa et al. 1996. PubMed ID: 8696350; Fonseca et al. 2008. PubMed ID: 21479481; Wenger et al. 2015. PMID: 25706251; Ron et al. 2016. PubMed ID: 27079505). This variant has also been identified as a de novo variant in an infant with a clinical diagnosis of Pfeiffer syndrome (Willig et al. 2015. PubMed ID: 25937001). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.