ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.644+1G>A

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809713 SCV000949883 likely pathogenic Methylmalonic aciduria cblB type 2018-12-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 8) of the MMAB 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 MMAB-related conditions. 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 variant is predicted to disrupts the C-terminus of the MMAB protein, which has been demonstrated to be important for enzymatic activity (PMID: 21604717). While functional studies have not been performed to directly test the effect of this variant on MMAB protein function, this suggests that disruption of this region of the 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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