Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000578705 | SCV000680713 | pathogenic | not provided | 2018-09-05 | criteria provided, single submitter | clinical testing | The E434X variant creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG). This variant has been reported in at least one individual with Birt-Hogg-Dube syndrome (Lim et al., 2010). Of note, this variant is located in the last nucleotide of exon 11, and multiple splicing models predict it may damage or destroy the nearby splice donor site. While functional analysis of this variant has not been performed, RT-PCR analysis of c.1300G>C (p.Glu434Gln) impacting the same nucleotide position showed skipping of exon 11 and has been reported in multiple individuals with Birt-Hogg-Dube syndrome (van Steensel et al., 2007; Toro et al., 2008). In the absence of RNA studies, the actual molecular effect of c.1300G>T is unknown; however, the effects at both the transcript and protein levels are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We therefore consider this variant to be pathogenic. |
| Invitae | RCV000807381 | SCV000947429 | pathogenic | Birt-Hogg-Dube syndrome | 2018-12-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in an individual affected with Birt-Hogg-Dubé syndrome (PMID: 19802896). ClinVar contains an entry for this variant (Variation ID: 488811). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu434*) in the FLCN gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002384274 | SCV002691169 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-07-27 | criteria provided, single submitter | clinical testing | The p.E434* pathogenic mutation (also known as c.1300G>T), located in coding exon 8 of the FLCN gene, results from a G to T substitution at nucleotide position 1300. This changes the amino acid from a glutamic acid to a stop codon within coding exon 8. This mutation was reported in an FLCN database in a patient with Birt-Hogg-Dubé syndrome (Lim DH et al. Hum. Mutat. 2010 Jan;31(1):E1043-51). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |