Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001390199 | SCV001591836 | pathogenic | Birt-Hogg-Dube syndrome | 2020-09-05 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the FLCN gene (p.Ala541Cysfs*61). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acids of the FLCN protein and extend the protein by an additional 21 amino acids. This variant has not been reported in the literature in individuals with FLCN-related conditions. This variant disrupts a portion of the C-terminus of the FLCN protein containing the minimal binding region for interaction with FNIP1/2 (residues 517-579) (PMID: 17028174, 18403135, 18663353, 22977732). Other variant(s) that disrupt this region (p.Trp553*) have been determined to be pathogenic (PMID: 28558743). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002404906 | SCV002707986 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-01-08 | criteria provided, single submitter | clinical testing | The c.1616dupT variant, located in coding exon 11 of the FLCN gene, results from a duplication of T at nucleotide position 1616, causing a translational frameshift with a predicted alternate stop codon (p.A541Cfs*61). This alteration occurs at the 3' terminus of theFLCN gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 20 amino acids. This frameshift impacts the last 7%/39AAamino acids of the native protein. However, frameshifts are typically deleterious in nature, and there are multiple similar alterations classified as pathogenic including FLCN c.1597_1598delCA (p.Q533Efs*68) and FLCN c.1579_1580insA (p.R527Qfs*75) (Ambry Internal Data; Furuya M et al. Am J Surg Pathol, 2012 Apr;36:589-600; Yang CY et al. J Postgrad Med;59:321-3; Liu L et al. Biomed Res Int, 2017 Jul;2017:8751384; Hou X et al. BMC Med Genet, 2018 01;19:14). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with FLCN-related disease (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001390199 | SCV004029920 | likely pathogenic | Birt-Hogg-Dube syndrome | 2023-07-11 | criteria provided, single submitter | clinical testing | Variant summary: FLCN c.1616dupT (p.Ala541CysfsX61) causes a frameshift which results in an extension of the protein. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant disrupts the last 39 amino acids in the encoded protein and extends the protein by 21 amino acids. Variants in this disrupted region have been previously classified as pathogenic (ClinVar 428647), suggesting this region of the FLCN protein may be clinically significant. The variant was absent in 251496 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1616dupT in individuals affected with Birt-Hogg-Dube Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |