Submissions for variant NM_023110.3(FGFR1):c.1333C>T (p.Arg445Trp)

gnomAD frequency: 0.00001  dbSNP: rs781608303

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001763255	SCV001990637	uncertain significance	not provided	2019-03-08	criteria provided, single submitter	clinical testing	Has been previously published in association with congenital anomalies of the kidney and urinary tract however, this publication is unavailable to GeneDx (van der Ven et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30143558)
Fulgent Genetics, Fulgent Genetics	RCV002489763	SCV002780762	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Jackson-Weiss syndrome; Pfeiffer syndrome; Hartsfield-Bixler-Demyer syndrome; Osteoglophonic dysplasia; Trigonocephaly 1; Encephalocraniocutaneous lipomatosis	2022-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479346	SCV004223681	uncertain significance	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: FGFR1 c.1333C>T (p.Arg445Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249416 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1333C>T has been reported in the literature in at least one individual affected with Congenital anomalies of the kidney and urinary tract (van der Ven_2018). The report does not provide unequivocal conclusions about association of the variant with FGFR1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30143558). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV003771975	SCV004605310	uncertain significance	Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome	2022-11-14	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae 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 FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1308343). This variant is also known as c.1426C>T, p.Arg476Trp. This missense change has been observed in individual(s) with clinical features of FGFR1-related conditions (PMID: 30143558). This variant is present in population databases (rs781608303, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 445 of the FGFR1 protein (p.Arg445Trp).