ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1A>G (p.Met1Val) (rs776806414)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498198 SCV000589882 likely pathogenic not provided 2016-06-15 criteria provided, single submitter clinical testing The c.1 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1 A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1 A>G variant alters an initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Functional analysis found that p.Met1? abolishes the first translation initiation codon thereby removing the mitochondrial leader sequence necessary for proper targeting and function in the TCA cycle (Dik et al. 2016). There is a second ATG in the FH gene at p.Met44 that initiates translation of the cystosolic form of the FH protein. It has been suggested that the cytosolic form of FH may play a role in DNA damage repair and thus act as a tumor suppressor (Dik et al. 2016). Therefore, we interpret the c.1 A>G variant as likely pathogenic in association with the autosomal recessive disorder fumarase deficiency as it destroys the mitochondrial leader sequence; however, as a cystosolic form of FH would still be produced from the second ATG codon. It is not certain whether the c.1 A>G variant may be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC)."
Invitae RCV000226429 SCV000283670 likely pathogenic Fumarase deficiency 2018-02-05 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 237113). 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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