Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000706446 | SCV000835495 | uncertain significance | Birt-Hogg-Dube syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 423 of the FLCN protein (p.His423Tyr). This variant is present in population databases (rs765628527, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 582392). 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 not expected to disrupt FLCN protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Ambry Genetics | RCV002369969 | SCV002684171 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-07 | criteria provided, single submitter | clinical testing | The p.H423Y variant (also known as c.1267C>T), located in coding exon 8 of the FLCN gene, results from a C to T substitution at nucleotide position 1267. The histidine at codon 423 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |