ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1391-1G>A (rs863223978)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466829 SCV000544241 likely pathogenic Fumarase deficiency 2017-07-31 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 9) of the FH gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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: 405909). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This splice acceptor site variant is expected to result in a disruption of exon 10. Several truncating variants in exon 10 (p.Gly490Alafs*12, p.Leu492Hisfs*6, p.Glu495Valfs*2, p.Trp500*) have been determined to be pathogenic (PMID: 12772087, 21404119, 16597677, 9635293, 21398687, Invitae database). This suggests that disruption of this region of the FH protein is causative of disease. 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.

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