Submissions for variant NM_000141.5(FGFR2):c.1694A>C (p.Glu565Ala)

dbSNP: rs121918506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000014219	SCV000328404	likely pathogenic	Pfeiffer syndrome	2016-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851848	SCV002153619	pathogenic	FGFR2-related craniosynostosis	2021-11-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 13294). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 15523615, 18541976, 24127277). 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 glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 565 of the FGFR2 protein (p.Glu565Ala).
3billion	RCV000014219	SCV002521346	pathogenic	Pfeiffer syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013294). A different missense change at the same codon (p.Glu565Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374823). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV003441716	SCV004170478	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18541976, 17803937, 15523615, 31911531, 34250419, 33218975, 24127277, 33731768, 33502061)
OMIM	RCV000014219	SCV000034467	pathogenic	Pfeiffer syndrome	2004-12-15	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434384	SCV000510534	likely pathogenic	Craniosynostosis syndrome	2016-05-13	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000014219	SCV001468143	pathogenic	Pfeiffer syndrome	2020-06-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532338	SCV004708975	pathogenic	FGFR2-related disorder	2024-01-18	no assertion criteria provided	clinical testing	The FGFR2 c.1694A>C variant is predicted to result in the amino acid substitution p.Glu565Ala. This variant has been reported in individuals with Pfeiffer syndrome (arisen de novo, Zankl et al. 2004. PubMed ID: 15523615; Freeman et al. 2008. PubMed ID: 18541976; Table S2, Wang et al. 2021. PubMed ID: 33502061) as well as an individual with Crouzon syndrome (Roscioli et al. 2013. PubMed ID: 24127277). In vitro functional studies demonstrate that expression of this variant results in a gain of function by constitutively activating the kinase activity of FGFR2 (Chen et al. 2007. PubMed ID: 17803937). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported by several laboratories as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13294/). Additionally, a different missense change impacting the same amino acid (p.Glu565Gly) has been reported to segregate with disease in a family with Pfeiffer syndrome (Kan et al. 2002. PubMed ID: 11781872), supporting the evidence that this amino acid may be important for FGFR2 function. Taken together, the p.Glu565Ala variant is interpreted as pathogenic.