ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1445T>G (p.Leu482Ter) (rs1064796708)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485484 SCV000573707 likely pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing The L482X nonsense variant in the FH gene has it been reported as a benign variant to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. Based on currently available evidence, L482X is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Invitae RCV000524801 SCV000632445 pathogenic Fumarase deficiency 2017-03-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the FH mRNA at codon 482 (p.Leu482*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 29 amino acids of the FH protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an FH-related disease. However, different truncating variants downstream of this variant (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 deletion of this region of the FH protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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