Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000802586 | SCV000942423 | pathogenic | Fumarase deficiency | 2018-11-17 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 7-10 of the FH gene. The 5' boundary is likely confined to intron 6. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated FH protein. An exon 7-10 deletion has been reported in an individual affected with hereditary leiomyomatosis and renal cell carcinoma (PMID: 28196407). Although no functional studies have assayed the effect of this particular deletion on FH protein function or stability, several truncating variants in the last exon (p.Gly490Alafs*12, p.Leu492Hisfs*6, p.Glu495Valfs*2, and p.Trp500*) have been determined to be likely pathogenic (PMID: 12772087, 21404119, 16597677, 9635293, 21398687, Invitae database). This suggests that the C-terminal region of the FH protein is critical for the proper protein function. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). For these reasons, this variant has been classified as Pathogenic. |