Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481922 | SCV000571273 | likely pathogenic | not provided | 2016-08-02 | criteria provided, single submitter | clinical testing | The M532T variant in the FGFR1 gene has been reported previously in a patient with combined pituitary hormone deficiency (Raivio et al., 2012). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Although, functional studies of the FGFR1 variant have shown that it results in an increase of ligand-dependent signaling, it remains unclear whether this increase corresponds to the phenotype in the individual (Raivio et al., 2012). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV002526617 | SCV003274929 | uncertain significance | Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome | 2022-12-14 | 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. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 22319038). 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) performed at Invitae indicates that this missense variant is expected to disrupt FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 421930). This missense change has been observed in individual(s) with FGFR1-related conditions (PMID: 22319038). This variant is present in population databases (rs777345476, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 532 of the FGFR1 protein (p.Met532Thr). |