Submissions for variant NM_023110.3(FGFR1):c.899T>C (p.Ile300Thr)

gnomAD frequency: 0.00042  dbSNP: rs121909633

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502492	SCV000594770	uncertain significance	not specified	2016-03-15	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514891	SCV000610054	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000766015	SCV000897452	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis	2018-10-31	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000502492	SCV000930355	uncertain significance	not specified	2019-04-27	criteria provided, single submitter	clinical testing
Invitae	RCV001407682	SCV001609659	likely benign	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000514891	SCV001793668	likely benign	not provided	2019-06-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16838304, 14513299, 19056490, 11173846, 24127277, 23329143, 27896051, 15793702)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000514891	SCV002011023	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532374	SCV004730697	likely benign	FGFR1-related disorder	2023-12-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000017681	SCV000037958	pathogenic	Trigonocephaly 1	2005-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000514891	SCV001552649	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FGFR1 p.Ile300Thr variant was identified in 1 of 10 patients with trigonocephaly but was not identified in 300 control chromosomes (Kress_2000_PMID: 11173846). The variant was also reported in 1 of 32 Antley-Bixler syndrome patients, however the patient with this variant was also compound heterozygous for two suspected pathogenic variants in the POR gene (Huang_2005_PMID: 15793702). The variant was identified in dbSNP (ID: rs121909633) and ClinVar (classified as uncertain significance by Fulgent Genetics, Children's Mercy Hospital, University of Chicago, and Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 84 of 280990 chromosomes at a frequency of 0.0002989 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 78 of 128708 chromosomes (freq: 0.000606), Other in 3 of 7152 chromosomes (freq: 0.00042), African in 2 of 24216 chromosomes (freq: 0.000083) and East Asian in 1 of 19538 chromosomes (freq: 0.000051), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), or South Asian populations. The p.Ile300 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514891	SCV001956046	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514891	SCV001965678	likely benign	not provided		no assertion criteria provided	clinical testing