Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000540340 | SCV000644846 | uncertain significance | Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 448 of the FGFR1 protein (p.Arg448Gln). This variant is present in population databases (rs758138124, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 468283). 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. 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. |
| ARUP Laboratories, |
RCV000757294 | SCV000885454 | uncertain significance | not provided | 2018-04-20 | criteria provided, single submitter | clinical testing | The FGFR1 c.1343G>A; p.Arg448Gln variant (rs758138124) has been identified in a patient diagnosed with idiopathic hypogonadotropic hypogonadism, and functional studies showed that this variant reduced but did not entirely abolish the protein’s ability to bind to the transcription factor EMX1 (Kim 2010). Another variant affecting this amino acid, p.Arg448Trp, has been reported as pathogenic for GnRH deficiency (Show 2011). The p.Arg448Gln variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.02% (identified on 6 out of 30,782chromosomes). The arginine at position 448 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg448Gln variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Although the available evidence is suggestive of pathogenicity, the clinical significance of the p.Arg448Gln variant cannot be determined with certainty. |
| Gene |
RCV000757294 | SCV001997458 | uncertain significance | not provided | 2019-09-05 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Ambry Genetics | RCV002528411 | SCV003563415 | uncertain significance | Inborn genetic diseases | 2021-07-20 | criteria provided, single submitter | clinical testing | The c.1343G>A (p.R448Q) alteration is located in exon 10 (coding exon 9) of the FGFR1 gene. This alteration results from a G to A substitution at nucleotide position 1343, causing the arginine (R) at amino acid position 448 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |