ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1A>T (p.Met1Leu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000794812 SCV000934244 likely pathogenic Fumarase deficiency 2018-09-08 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the FH mRNA. The next in-frame methionine is located at codon 44. While this variant is present in population databases (rs776806414), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with FH-related disease. The mature human fumarate hydratase (FH) protein is localized in both the mitochondrial and cytosolic cellular compartments (PMID: 21929734). Within the first exon of the FH gene there are two in-frame initiator methionines, Met1 and Met44, with the mitochondrial targeting sequence lying between these two translational start sites. An experimental study has shown that the two FH protein echoforms arise from separate mRNA transcripts derived by alternative transcriptional initiation, which are translated and localized to either the mitochondria or cytosol based on initiation from Met1 or Met44, respectively (PMID: 27037871). Therefore, this variant is likely to disrupt the mitochondrial-localized FH protein, while not altering the cytosol-localized protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic for autosomal recessive fumarate hydratase deficiency. However, this variant is not likely to confer risk for autosomal dominant hereditary leiomyomatosis and renal cell cancer.

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