Total submissions: 35
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Juno Genomics, |
RCV004795407 | SCV005418693 | pathogenic | Acrocephalosyndactyly type I; Beare-Stevenson cutis gyrata syndrome; Jackson-Weiss 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; LADD syndrome 1 | criteria provided, single submitter | clinical testing | PM2_Supporting+PS4+PS3+PS2 | |
| Institute of Human Genetics, |
RCV000014191 | SCV005368082 | pathogenic | Acrocephalosyndactyly type I | 2024-06-07 | criteria provided, single submitter | clinical testing | Criteria applied: PS2,PS4,PS3_MOD,PM2_MOD,PP3 |
| Clinical Genetics Laboratory, |
RCV000263144 | SCV005197922 | pathogenic | not provided | 2022-07-13 | criteria provided, single submitter | clinical testing | |
| Breakthrough Genomics, |
RCV000014191 | SCV005088771 | pathogenic | Acrocephalosyndactyly type I | 2022-04-11 | criteria provided, single submitter | clinical testing | This variant has been reported as a recurrent variant in Apert syndrome, accounting for disease in approximately 71% of affected individuals and families. It segregates with the disease in several families with multiple affected individuals [PMID: 7719344, 8651276, 25867380, 9462761, 12124745, 23546041]. Functionall studies have shown that the variant exerts a gain-of-function effect by enhancing FGFR2 binding affinity [PMID: 11390973, 22664175, 23495007, 24489893]. |
| Genomic Medicine Center of Excellence, |
RCV004527288 | SCV005038841 | pathogenic | Pfeiffer syndrome | 2024-03-14 | criteria provided, single submitter | clinical testing | |
| Division of Human Genetics, |
RCV000552015 | SCV004123087 | pathogenic | FGFR2-related craniosynostosis | 2023-07-01 | criteria provided, single submitter | research | |
| Rady Children's Institute for Genomic Medicine, |
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. | |
| Genesolutions, |
RCV000014191 | SCV003934959 | pathogenic | Acrocephalosyndactyly type I | 2022-06-22 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV000014191 | SCV003841499 | pathogenic | Acrocephalosyndactyly type I | 2023-10-17 | 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: 0.0004%). Predicted Consequence/Location: 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 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.60 (>=0.6, sensitivity 0.72 and precision 0.9)]. 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. |
| Laboratorio de Genetica e Diagnostico Molecular, |
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 |
| MGZ Medical Genetics Center | RCV000014191 | SCV002580222 | pathogenic | Acrocephalosyndactyly type I | 2021-07-30 | criteria provided, single submitter | clinical testing | |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
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). |
| Neuberg Centre For Genomic Medicine, |
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. | |
| 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. |
| Revvity Omics, |
RCV000263144 | SCV002023062 | pathogenic | not provided | 2023-10-26 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV000263144 | SCV001832423 | pathogenic | not provided | 2019-11-30 | criteria provided, single submitter | clinical testing | |
| Knight Diagnostic Laboratories, |
RCV000014191 | SCV001448735 | pathogenic | Acrocephalosyndactyly type I | 2019-09-20 | criteria provided, single submitter | clinical testing | |
| Department of Medical Genetics, |
RCV000014191 | SCV001437545 | pathogenic | Acrocephalosyndactyly type I | criteria provided, single submitter | clinical testing | ||
| Ce |
RCV000263144 | SCV001247453 | pathogenic | not provided | 2023-05-01 | criteria provided, single submitter | clinical testing | FGFR2: PS2, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting |
| Johns Hopkins Genomics, |
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. |
| 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 | |
| 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). |
| Labcorp Genetics |
RCV000552015 | SCV000659618 | pathogenic | FGFR2-related craniosynostosis | 2025-01-29 | criteria provided, single submitter | clinical testing | 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). This variant is present in population databases (rs79184941, gnomAD 0.007%). 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. ClinVar contains an entry for this variant (Variation ID: 13272). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR2 protein function. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000263144 | SCV000329832 | pathogenic | not provided | 2025-05-20 | criteria provided, single submitter | clinical testing | Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect resulting in altered receptor affinity and upregulation of FGF signaling leading to the dysregulation of genes involved in bone formation, bone mineralization and osteoclastogenesis (PMID: 23519026, 9700203, 24489893, 31064775); 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: 31879841, 28316926, 16440883, 19186770, 31387623, 34367232, 7719344, 23754559, 23495007, 22664175, 25867380, 9700203, 22105374, 10067911, 23593218, 24489893, 25297884, 9462761, 22048896, 23546041, 21154333, 25045033, 25433548, 27228464, 18215098, 28976722, 16951439, 29483804, 8651276, 30355600, 29753329, 30656008, 15282208, 30679815, 9719378, 16906598, 29037998, 30657466, 31064775, 30719288, 31502745, 30672749, 31837199, 31019026, 32954549, 34645491, 33249554, 36376059, 36398383, 34627339, 37204857, 35982159, 10658283, 32510873, 8676562, 33937142, 35088901, 35591945, 33585639, 34958143, 34358384, 34094714, 31145570, 23519026, 38702915, 38253798, 11781872, 29230096, 36352425, 33057194, 39906733, 36307859, 37745857, 38246420) |
| Genomic Diagnostic Laboratory, |
RCV000014191 | SCV000328367 | pathogenic | Acrocephalosyndactyly type I | 2016-09-17 | criteria provided, single submitter | clinical testing | |
| Programa de Pós- |
RCV000014191 | SCV000223905 | pathogenic | Acrocephalosyndactyly type I | 2015-04-01 | criteria provided, single submitter | research | |
| Prevention |
RCV004532334 | SCV004736613 | pathogenic | FGFR2-related disorder | 2024-01-13 | no assertion criteria provided | 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. |
| Institute Of Reproduction And Development, |
RCV000014191 | SCV003844078 | pathogenic | Acrocephalosyndactyly type I | 2021-09-16 | no assertion criteria provided | research | |
| Department of Genetics, |
RCV000014191 | SCV002540763 | pathogenic | Acrocephalosyndactyly type I | 2022-06-29 | no assertion criteria provided | research | |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000263144 | SCV001971109 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000263144 | SCV001956035 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratory of Diagnostic Genome Analysis, |
RCV000263144 | SCV001798214 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Gene |
RCV000014191 | SCV000929990 | not provided | Acrocephalosyndactyly type I | no assertion provided | literature only | ||
| OMIM | RCV000014192 | SCV000034440 | pathogenic | Endometrial carcinoma | 2007-11-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000014191 | SCV000034439 | pathogenic | Acrocephalosyndactyly type I | 2007-11-01 | no assertion criteria provided | literature only |