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

gnomAD frequency: 0.00004  dbSNP: rs369296618

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln234*) in the MMAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the MMAB protein. This variant is present in population databases (rs369296618, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 203820). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MMAB function (PMID: 21604717). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000190603	SCV004193132	pathogenic	Methylmalonic aciduria, cblB type	2023-10-26	criteria provided, single submitter	clinical testing
GeneReviews	RCV000190603	SCV000258533	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Natera, Inc.	RCV000190603	SCV001459235	pathogenic	Methylmalonic aciduria, cblB type	2020-09-16	no assertion criteria provided	clinical testing
Baumgartner lab, University Children's Hospital Zurich	RCV000190603	SCV001738806	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing