ClinVar Miner

Submissions for variant NM_000143.4(FH):c.1251dup (p.His418fs)

dbSNP: rs1553340708
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002527718 SCV000632438 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing This variant disrupts the last 92 amino acid residues (His418-Lys510) of the full-length FH protein. While this particular variant has not been reported in the literature, a downstream truncating variant (p.Trp500*) deleting the last 11 amino acids has been observed in an individual with fumarate hydratase deficiency (PMID: 9635293, 20549362). It was also shown to segregate with disease in a large family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 21398687). This suggests that C-terminal truncation of FH is deleterious to protein function and may be pathogenic. For these reasons, this variant has been classified as Pathogenic. In addition, a missense substitution at codon 419 (p.Ser419Pro) has been determined to be likely pathogenic (PMID: 16597677, 15937070). This suggests that the serine residue, which is disrupted by this frameshift variant, is critical for FH protein function and that other substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FH gene (p.His418Thrfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 92 amino acid residues of the FH protein.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.