ClinVar Miner

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

dbSNP: rs79184941
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Total submissions: 37
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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
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, 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 2019-12-24 criteria provided, single submitter clinical testing Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect by changing receptor affinity to its ligands; FGF signaling is upregulated compared to wild type, leading to dysregulation of genes involved in bone formation, bone mineralization and osteoclastogenesis (Anderson et al., 1998; Martinez-Abadias et al., 2013; Chen et al., 2014; Motch Perrine et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31879841, 28316926, 16440883, 19186770, 31387623, 7719344, 23754559, 23495007, 22664175, 23519026, 25867380, 9700203, 22105374, 10067911, 23593218, 24489893, 25297884, 9462761, 22048896, 23546041, 21154333, 25045033, 25433548, 27228464, 18215098, 28976722, 16951439, 29483804, 8651276, 30355600, 29753329, 30656008, 20301628, 15282208, 30679815, 9719378, 16906598, 29037998, 30657466, 31064775, 30719288, 31502745, 30672749, 31837199, 31019026, 32954549, 10658283, 32510873, 8676562, 33937142)
Invitae RCV000552015 SCV000659618 pathogenic FGFR2-related craniosynostosis 2023-08-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893). 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: 13272). This missense change has been observed in individual(s) with Apert syndrome, accounting for disease in approximately 71% of affected individuals and families (PMID: 7719344, 8651276, 9462761, 25867380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs79184941, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the FGFR2 protein (p.Ser252Trp).
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 RCV002476961 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; Familial scaphocephaly syndrome, McGillivray type; Bent bone dysplasia syndrome 1; Gastric cancer 2021-08-12 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 Center for Human Genetics Tuebingen RCV000263144 SCV001247453 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing FGFR2: PS2, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting
Department of Medical Genetics, Oslo University Hospital RCV000014191 SCV001437545 pathogenic Acrocephalosyndactyly type I criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000014191 SCV001448735 pathogenic Acrocephalosyndactyly type I 2019-09-20 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000263144 SCV001832423 pathogenic not provided 2019-11-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000263144 SCV002023062 pathogenic not provided 2023-10-26 criteria provided, single submitter clinical testing
DASA RCV000552015 SCV002061183 pathogenic FGFR2-related craniosynostosis 2022-01-05 criteria provided, single submitter clinical testing The c.755C>G;p.(Ser252Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13272; PMID: 24489893; 25867380; 26380986; 31145570) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24489893) - PS3_moderate. This variant is not present in population databases (rs79184941, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in FGFR2 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV000014191 SCV002073300 pathogenic Acrocephalosyndactyly type I criteria provided, single submitter clinical testing The missense variant p.S252W in FGFR2 (NM_000141.4) has been previously reported as a common mutation in Apert Syndrome (Polla D et al, 2015). Functional studies demonstrate a constituional activation of FGFR2 (Ibrahimi et al, 2001). The variant has been submitted to ClinVar as Pathogenic. The missense variant c.755C>G (p.S252W) in FGFR2 (NM_000141.5) is observed in 1/16152 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict a damaging effect and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV000014191 SCV002525629 pathogenic Acrocephalosyndactyly type I 2021-02-17 criteria provided, single submitter clinical testing This is a recurrent pathogenic variant that has previously been reported in several unrelated individuals with Apert syndrome and other FGFR2-associated craniosynostosis syndromes (NBK541728). It is one of the most commonly detected variants in individuals with Apert syndrome accounting for approximately 60-70% of cases (NBK541728). This variant has been observed in one individual in the Genome Aggregation Database (1 of 249,864 alleles; v2.1.1). The c.755C>G variant is predicted to replace the serine at codon 252 with tryptophan and experimentally shown to result in a gain of function of FGFR2 (PMID: 9700203).
MGZ Medical Genetics Center RCV000014191 SCV002580222 pathogenic Acrocephalosyndactyly type I 2021-07-30 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000014191 SCV003807349 pathogenic Acrocephalosyndactyly type I 2022-09-22 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP1 supporting, PP3 supporting
3billion RCV000014191 SCV003841499 pathogenic Acrocephalosyndactyly type I 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). 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: 0.80; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013272 / PMID: 7719344 / 3billion dataset). A different missense change at the same codon (p.Ser252Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013279 / PMID: 9002682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam RCV000014191 SCV003934959 pathogenic Acrocephalosyndactyly type I 2022-06-22 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004532334 SCV004046053 pathogenic FGFR2-related disorder criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in individuals with Apert syndrome (PMID: 7719344, 8651276, 9462761, 25867380). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/249864). The c.755C>G (p.Ser252Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.755C>G (p.Ser252Trp) variant is classified as Pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000552015 SCV004123087 pathogenic FGFR2-related craniosynostosis 2023-07-01 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV004532334 SCV004736613 pathogenic FGFR2-related disorder 2024-01-13 criteria provided, single submitter clinical testing The FGFR2 c.755C>G variant is predicted to result in the amino acid substitution p.Ser252Trp. This variant is the most common recurrent variant reported in patients with Apert syndrome (Wilkie et al. 1995. PubMed ID: 7719344, reported as c.934C>G; Passos-Bueno et al. 1998. PubMed ID: 9719378; Polla et al. 2015. PubMed ID: 26380986; Kunwar et al. 2017. PubMed ID: 28316926). The variant is observed once in population databases indicating this variant is rare. In summary, this variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV004527288 SCV005038841 pathogenic Pfeiffer syndrome 2024-03-14 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 Endometrium 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 Gastric adenocarcinoma 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 not provided Acrocephalosyndactyly type I no assertion provided literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000263144 SCV001798214 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000263144 SCV001956035 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000263144 SCV001971109 pathogenic not provided no assertion criteria provided clinical testing
Department of Genetics, Beijing BioBiggen Technology Co., Ltd. RCV000014191 SCV002540763 pathogenic Acrocephalosyndactyly type I 2022-06-29 no assertion criteria provided research
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University RCV000014191 SCV003844078 pathogenic Acrocephalosyndactyly type I 2021-09-16 no assertion criteria provided research

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