ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2125-3C>G

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000813589 SCV000953955 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-12-12 criteria provided, single submitter clinical testing This sequence change falls in intron 12 of the MUT gene. It does not directly change the encoded amino acid sequence of the MUT protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with methylmalonic acidura (PMID: 26449400, 27602322). 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 demonstrated to disrupt the last 42 amino acids of the MUT protein (PMID: 26449400, 27602322), including the p.Gly717 residue. Other variant(s) that disrupt this residue have been observed in individuals with MUT-related conditions (PMID: 1346616, 16281286, 27233228), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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