Submissions for variant NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)

dbSNP: rs4647924

Total submissions: 46

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193831	SCV000247376	pathogenic	Craniosynostosis syndrome	2015-04-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000017746	SCV000328408	pathogenic	Muenke syndrome	2016-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000436385	SCV000521019	pathogenic	not provided	2020-11-27	criteria provided, single submitter	clinical testing	Reported in multiple individuals with features overlapping other craniosynostosis syndromes, including Pfeiffer syndrome, Crouzon syndrome, and Saethre-Chotzen syndrome (Bellus et al., 1996; Muenke et al., 1997; Mulliken et al., 1999; Kruszka et al., 2016); however, some of the clinical features of individuals with the above syndromes may be rare in patients with this variant (Muenke et al., 1997); Reported in some individuals with radiographic abnormalities of hands and feet but without craniosynostosis, having normal head size or macrocephaly (Muenke et al., 1997; Kruszka et al., 2016a); Published functional studies demonstrate a damaging effect including disruption of endochondral and perichondrial ossification of the cranial base in mice (Laurita et al., 2011; Yasuda et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 11746040, 22622662, 24127277, 28551036, 31837199, 14613973, 26740388, 11424131, 12884424, 23325524, 19449410, 21204234, 22016144, 24705944, 15915095, 21233754, 21403567, 22446440, 23851839, 20592905, 24168007, 11197897, 24728327, 12087222, 20707699, 11428324, 8841188, 10541159, 27683237, 27568649, 26028288, 9279764, 9600744, 17103449, 17036334, 31111620, 31130284, 9042914, 20301588, 32238909, 31564432, 31019026, 32369273, 32382396, 9107244, 18000976, 32510873, 33502061)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000436385	SCV000640386	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 250 of the FGFR3 protein (p.Pro250Arg). This variant is present in population databases (rs4647924, gnomAD 0.003%). This missense change has been observed in individual(s) with Muenke syndrome, but has also been identified in individuals with features of Saethre-Chotzen syndrome or other craniosynostosis syndromes (PMID: 9042914, 10094188, 10861678, 15915095, 26740388). 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: 16340). 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 FGFR3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 14613973). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622712	SCV000740868	pathogenic	Inborn genetic diseases	2023-03-21	criteria provided, single submitter	clinical testing	The c.749C>G (p.P250R) alteration is located in exon 7 (coding exon 6) of the FGFR3 gene. This alteration results from a C to G substitution at nucleotide position 749, causing the proline (P) at amino acid position 250 to be replaced by an arginine (R)._x000D_ _x000D_ Based on the available evidence, the FGFR3 c.749C>G (p.P250R) alteration is classified as pathogenic for Muenke syndrome. Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/270300) total alleles studied. The highest observed frequency was 0.003% (1/34950) of Latino alleles. The FGFR3 c.749C>G (p.P250R) alteration is a well-established disease-causing alteration of Muenke syndrome and the only reported pathogenic mutation in patients with Muenke syndrome (Bellus, 1996; Kruszka, 2016). This amino acid position is well conserved in available vertebrate species. Functional analysis of mouse models of Muenke syndrome harboring the mouse equivalent of the p.P250R alteration (p.P244R in mice) show that the alteration disrupts endochondral and perichondrial ossification in the cranial base (Laurita, 2011) as well as the temporomandibular joint development by reducing hedgehog signaling and endochondral ossification (Laurita, 2011; Yasuda, 2012). Surface plasmon resonance analysis and X-ray crystallography demonstrated enhanced binding of the mutant structure compared to wildtype (Ibrahimi, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626772	SCV000747475	pathogenic	Crouzon syndrome; Seizure; Unilateral renal agenesis; Facial asymmetry; Generalized non-motor (absence) seizure; Coronal craniosynostosis; Infantile axial hypotonia	2017-01-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000436385	SCV000861668	pathogenic	not provided	2018-06-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003375	SCV000893665	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Colorectal cancer; Germ cell tumor of testis; Lacrimoauriculodentodigital syndrome 2	2024-06-19	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000017746	SCV000996136	pathogenic	Muenke syndrome	2018-04-24	criteria provided, single submitter	clinical testing	This variant is a well-established cause of Muenke syndrome (PMID: 9042914, 26740388, 20301628). Functional characterization demonstrates that this missense change enhances ligand-binding in vitro compared to wild-type and affects endochondral ossification (PMID: 14613973, 22016144). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.001% (2/267,378) and is thus presumed to be rare. It is a non-conservative amino acid substitution and is predicted by multiple in silico tools to be deleterious to protein function. Based on the combined evidence, the c.749C>G (p.Pro250Arg) variant is classified as pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000017746	SCV000999367	pathogenic	Muenke syndrome		criteria provided, single submitter	clinical testing
Mendelics	RCV000987393	SCV001136681	pathogenic	Hypochondroplasia	2019-05-28	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000017746	SCV001160790	likely pathogenic	Muenke syndrome	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS3, PP2, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000436385	SCV001247231	pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	FGFR3: PS2:Very Strong, PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3
Department of Medical Genetics, Oslo University Hospital	RCV000017746	SCV001437547	pathogenic	Muenke syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334261	SCV001527055	pathogenic	Achondroplasia	2018-07-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The p.R250R pathogenic variant is the most common pathogenic variant found in MNKS patients with variable expressivity [PMID 9107244, 9279764]
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813993	SCV001755233	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000436385	SCV001832430	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000017746	SCV001934470	pathogenic	Muenke syndrome	2021-03-05	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Revvity Omics, Revvity	RCV000436385	SCV002023067	pathogenic	not provided	2019-09-27	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000017746	SCV002525634	pathogenic	Muenke syndrome	2022-02-04	criteria provided, single submitter	clinical testing	Muenke syndrome (MIM #602849) is diagnosed based on the presence of the recurrent p.Pro250Arg variant (PMID: 8841188).
Genetics and Molecular Pathology, SA Pathology	RCV000017746	SCV002556384	pathogenic	Muenke syndrome	2021-02-22	criteria provided, single submitter	clinical testing	The FGFR3 c.749C>G variant is a single nucleotide change in the FGFR3 gene that changes the amino acid proline at position 250 in the protein to arginine. This variant has been previously reported in several unrelated patients with Muenke syndrome (PMID: 9042914, 26740388, 20301628) (PS4_moderate). Functional characterization demonstrates that this missense change enhances ligand-binding in vitro compared to wild-type and affects endochondral ossification (PMID: 14613973, 22016144) (PS3). The variant was detected de novo in a patient with no family history of the disease (PS2). This variant has been reported in dbSNP (rs4647924) and is rare in population databases (2/270,300 in gnomAD, 0 homozygotes) (PM2). It is a non-conservative amino acid substitution and is predicted by multiple in silico tools to be deleterious to protein function (PP3).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273933	SCV002558894	pathogenic	FGFR3-related chondrodysplasia		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000017746	SCV002570288	pathogenic	Muenke syndrome	2022-02-28	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000017746	SCV002577535	pathogenic	Muenke syndrome	2021-12-20	criteria provided, single submitter	clinical testing	PS4, PM2, PP3, PP5
MGZ Medical Genetics Center	RCV000017746	SCV002581897	pathogenic	Muenke syndrome	2022-09-05	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000017746	SCV002771881	pathogenic	Muenke syndrome	2022-12-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000017746	SCV003807911	pathogenic	Muenke syndrome	2022-08-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM6 strong, PP3 supporting
Suma Genomics	RCV000017746	SCV003852618	pathogenic	Muenke syndrome		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017746	SCV003921920	pathogenic	Muenke syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMID: 25614871, PMID: 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, PMID: 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, PMID: 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (2 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is very well established as pathogenic, and has been reported in many individuals with Muenke syndrome with variable expressivity. Additionally, it has been observed less commonly in individuals with Saethre-Chotzen or craniosynostosis syndrome, and can be inherited from an asymptomatic parent (ClinVar, PMID: 26740388). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001334261	SCV004805169	pathogenic	Achondroplasia	2024-03-17	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004554603	SCV005043957	pathogenic	FGFR3-related disorder	2024-03-26	criteria provided, single submitter	clinical testing	PS2_Very Strong, PS3, PM1, PM5_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001334261	SCV005077050	pathogenic	Achondroplasia	2024-04-22	criteria provided, single submitter	clinical testing	Variant summary: FGFR3 c.749C>G (p.Pro250Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238970 control chromosomes. c.749C>G has been reported in the literature in multiple individuals affected with Muenke syndrome (example, Paumard-Hernandez_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhancement in ligand binding in vitro (Ibrahimi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14613973, 25271085). ClinVar contains an entry for this variant (Variation ID: 16340). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000436385	SCV005197925	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000017746	SCV005420725	pathogenic	Muenke syndrome	2024-10-04	criteria provided, single submitter	research	PS1, PS3, PM2
3billion	RCV000987393	SCV005906158	pathogenic	Hypochondroplasia	2023-08-04	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%). 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: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016340 /PMID: 8841188 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Pro250Leu, p.Pro250Thr) have been reported to be associated with FGFR3-related disorder (PMID: 12362036, 31721094). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Daryl Scott Lab, Baylor College of Medicine	RCV004554603	SCV005911547	pathogenic	FGFR3-related disorder	2024-04-01	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM2
OMIM	RCV000017746	SCV000038024	pathogenic	Muenke syndrome	2009-02-01	no assertion criteria provided	literature only
OMIM	RCV000017747	SCV000038025	pathogenic	Saethre-Chotzen syndrome	2009-02-01	no assertion criteria provided	literature only
ITMI	RCV000121075	SCV000085243	not provided	not specified	2013-09-19	no assertion provided	reference population
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000017746	SCV001469215	pathogenic	Muenke syndrome	2020-05-06	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000436385	SCV001808971	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000436385	SCV001952168	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000436385	SCV001969785	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000017746	SCV003927907	pathogenic	Muenke syndrome	2023-04-01	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483434	SCV004228601	not provided	Achondroplasia; Crouzon syndrome-acanthosis nigricans syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Hypochondroplasia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-18-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004554603	SCV005349592	pathogenic	FGFR3-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The FGFR3 c.749C>G variant is predicted to result in the amino acid substitution p.Pro250Arg. This variant has been documented as one of the most common variants associated with syndromic craniosynostosis, and in particular with autosomal dominant Muenke syndrome (Muenke et al. 1997. PubMed ID: 9042914; Mulliken et al. 1999. PubMed ID: 10541159; Roscioli et al. 2013. PubMed ID: 24127277; Kruszka et al. 2016. PubMed ID: 26740388). Of note, this variant has been reported in one patient without craniosynostosis but with hearing loss and developmental delay (Patient 15, Table 1, Kruszka et al. 2016. PubMed ID: 26740388). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.