ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.700C>T (p.Gln234Ter) (rs369296618)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000420410 SCV000511554 pathogenic not provided 2016-10-10 criteria provided, single submitter clinical testing
GeneReviews RCV000190603 SCV000258533 pathogenic Methylmalonic aciduria cblB type 2016-01-07 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000780427 SCV000917671 pathogenic Methylmalonic acidemia 2018-12-17 criteria provided, single submitter clinical testing Variant summary: MMAB c.700C>T (p.Gln234X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 246252 control chromosomes. c.700C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2006, O'Shea_2012). One publication reports that ibroblasts from patients with this mutation in homozygous or heterozygous form had higher levels of MCM function than most cblB fibroblasts however that was not found to correlated with any reduction in severity of clinical presentation (Lerner-Ellis_2006). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000190603 SCV000938483 pathogenic Methylmalonic aciduria cblB type 2019-01-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MMAB gene (p.Gln234*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acids of the MMAB protein. This variant is present in population databases (rs369296618, ExAC 0.006%). This variant has been observed in several individuals affected with methylmalonic aciduria (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 203820). This variant has been reported to affect MMAB protein function (PMID: 21604717). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000190603 SCV000245632 pathogenic Methylmalonic aciduria cblB type 2014-11-10 criteria provided, single submitter clinical testing The p.Gln234X variant in MMAB has been reported in 4 compound heterozygous and 2 homozygous individuals with methylmalonic aciduria (Lerner-Ellis 2006). This variant has been identified in 0.012% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs369296618). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 234. This alteration occurs within the last exon and is therefore more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that the p.Gln234X variant may impact protein function (Lofgren 2011); however, in vitro assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln234X variant is likely pathogenic.

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