Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001064646 | SCV001229557 | pathogenic | Cobalamin C disease | 2019-11-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MMACHC protein. Other variant(s) that disrupt this region (p.Val183Thrfs*5) have been determined to be pathogenic (PMID: 16311595, 19370762, 23954310). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. 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 has not been reported in the literature in individuals with MMACHC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 3) of the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. |