ClinVar Miner

Submissions for variant NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp) (rs79184941)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia,Universidade Católica de Brasília RCV000014191 SCV000223905 pathogenic Acrocephalosyndactyly type I 2015-04-01 criteria provided, single submitter research
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000014191 SCV000328367 pathogenic Acrocephalosyndactyly type I 2016-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000263144 SCV000329832 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The S252W pathogenic variant in the FGFR2 gene is a recurrent variant that is identified in approximately 70% of individuals with Apert syndrome (Robin et al., 2011). It has been reported as an assumed de novo variant in individuals with sporadic Apert syndrome, and it segregates with Apert syndrome in several families with multiple affected individuals (Wilkie et al., 1995; Slaney et al., 1996; Mundhofir et al., 2013). The S252W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S252W variant is a non-conservative amino acid substitution that alters a conserved position in the protein. Functional studies demonstrate that it is a gain-of-function variant that results in constitutive activation of FGFR2 and alters receptor binding activity (Ibrahimi et al., 2001; Robin et al., 2011). We interpret S252W as a pathogenic variant.
Invitae RCV000552015 SCV000659618 pathogenic FGFR2 related craniosynostosis 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 252 of the FGFR2 protein (p.Ser252Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is present in population databases (rs79184941, ExAC 0.01%). This variant is clearly defined as an Apert syndrome causative allele, accounting for disease in approximately 71% of affected individuals and families (PMID: 7719344, 8651276, 25867380, 9462761). It has been observed as de novo in several cases (PMID: 7719344, 9462761). ClinVar contains an entry for this variant (Variation ID: 13272). Experimental studies have shown that this missense change exerts a gain-of-function effect by enhancing FGFR2 binding affinity and recapitulates disease in mouse models (PMID: 11390973, 22664175, 23495007, 24489893). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000014191 SCV000883242 pathogenic Acrocephalosyndactyly type I 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Pathogenic, for Apert syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/14499350) (https://www.ncbi.nlm.nih.gov/pubmed/24489893) (https://www.ncbi.nlm.nih.gov/pubmed/15975938). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/23546041).
Fulgent Genetics,Fulgent Genetics RCV000762804 SCV000893154 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; Scaphocephaly, maxillary retrusion, and mental retardation; Neoplasm of stomach; Bent bone dysplasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000014191 SCV000925947 pathogenic Acrocephalosyndactyly type I 2019-03-18 criteria provided, single submitter clinical testing This FGFR2 variant (rs79184941) has been identified in 71% of patients with Apert syndrome and is rare in large population datasets (gnomAD: 1/249864 total alleles; 0.0004%; no homozygotes). It has been reported as an assumed de novo variant and has been shown to segregate with disease in multiple families. Six submitters in ClinVar classify FGFR2 c.755C>G as pathogenic. Functional studies have demonstrated that this variant shows a gain-of-function effect by enhancing FGFR2 ligand binding affinity. This variant is considered pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000263144 SCV001247453 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
OMIM RCV000014191 SCV000034439 pathogenic Acrocephalosyndactyly type I 2007-11-01 no assertion criteria provided literature only
OMIM RCV000014192 SCV000034440 pathogenic Endometrial carcinoma 2007-11-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431027 SCV000504809 likely pathogenic Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation 2014-12-26 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438603 SCV000504810 likely pathogenic Endometrial neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433942 SCV000506412 likely pathogenic Acrocephalosyndactyly 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440715 SCV000506413 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422979 SCV000506414 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433250 SCV000506415 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
GeneReviews RCV000014191 SCV000929990 pathogenic Acrocephalosyndactyly type I 2019-05-20 no assertion criteria provided literature only

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