Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000492176 | SCV000580742 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-27 | criteria provided, single submitter | clinical testing | The p.W553R variant (also known as c.1657T>C), located in coding exon 11 of the FLCN gene, results from a T to C substitution at nucleotide position 1657. The tryptophan at codon 553 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with a personal or family history that is consistent with FLCN-associated disease (Ambry internal data). Based on internal structural assessment, this alteration disrupts the C-terminal DENN-like domain, which is a guanine nucleotide exchange factor implicated in FLCN’s role in membrane trafficking (Ambry internal data; Nookala RK et al. Open Biol, 2012 Aug;2:120071; Dodding MP. Small GTPases, 2017 04;8:100-105; Schmidt LS et al. Gene, 2018 Jan;640:28-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV000690635 | SCV000818332 | pathogenic | Birt-Hogg-Dube syndrome | 2021-10-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 428647). This missense change has been observed in individuals with clinical features of Birt-Hogg-Dubé syndrome (Invitae; external communications). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 553 of the FLCN protein (p.Trp553Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. |
Gene |
RCV001584204 | SCV001820756 | likely pathogenic | not provided | 2023-09-14 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17028174) |
Fulgent Genetics, |
RCV002496889 | SCV002811592 | likely pathogenic | Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Nonpapillary renal cell carcinoma; Colorectal cancer | 2021-11-08 | criteria provided, single submitter | clinical testing |