Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480479 | SCV000565001 | likely pathogenic | not provided | 2014-12-24 | criteria provided, single submitter | clinical testing | The T340M variant that is likely disease-causing in the FGFR1 gene has been reported previously in association with Kallmann syndrome, although no additional information was provided regarding family studies (Dode et al., 2009). It was not observed in approximately 6,400 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. T340M 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 highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S332C, Y339C, C341W, L342S, A343V) have been reported in the Human Gene Mutation Database in association with Kallmann syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. |
| Medical Genetics Center, |
RCV003168938 | SCV003915619 | likely pathogenic | Hartsfield-Bixler-Demyer syndrome | 2021-07-27 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003766656 | SCV004569700 | uncertain significance | Hypogonadotropic hypogonadism 2 with or without anosmia; Pfeiffer syndrome | 2023-05-27 | 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: 418207). This missense change has been observed in individuals with idiopathic hypogonadotropic hypogonadism and/or Kallmann syndrome (PMID: 24031091, 31748124, 33983622). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 340 of the FGFR1 protein (p.Thr340Met). |