ClinVar Miner

Submissions for variant NM_015506.2(MMACHC):c.271dupA (rs398124292)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507720 SCV000604238 pathogenic not specified 2016-09-05 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081737 SCV000511400 pathogenic not provided 2016-07-13 criteria provided, single submitter clinical testing
Counsyl RCV000001486 SCV000485821 pathogenic Methylmalonic acidemia with homocystinuria 2016-11-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081737 SCV000331024 pathogenic not provided 2015-07-27 criteria provided, single submitter clinical testing
GeneDx RCV000081737 SCV000238996 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The c.271dupA pathogenic variant in the MMACHC gene has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006; Richard et al., 2009). In one large study of 204 patients with cblC deficiency, the c.271dupA variant accounted for 40% of all disease alleles (Lerner-Ellis, et al., 2006). The c.271dupA variant causes a frameshift starting with codon Arginine 91, changing it to Lysine, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Arg91LysfsX14. This variant is predicted to result in nonsense-mediated mRNA decay or in protein truncation. Therefore, c.271dupA is interpreted to be a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000001486 SCV000923540 uncertain significance Methylmalonic acidemia with homocystinuria 2019-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000308836 SCV000357919 pathogenic Disorders of Intracellular Cobalamin Metabolism 2017-10-26 criteria provided, single submitter clinical testing The MMACHC c.271dupA (p.Arg91LysfsTer14) variant, also referred to as c.270_271insA, results in a frameshift variant and is predicted to result in premature termination of the protein. The p.Arg91LysfsTer14 variant is well described in the literature and is reported as the most common pathogenic variant in the MMACHC gene accounting for approximately 40% of disease alleles (Manoli et al. 2016). The variant has been reported in at least 12 studies in which it was found in over 270 individuals with disorders of intracellular cobalamin metabolism, including at least 127 in a homozygous state and 143 in a compound heterozygous state (Lerner-Ellis et al. 2006; Morel et al. 2006; Heil et al. 2007; Nogueira et al. 2008; Lerner-Ellis et al. 2009; Perez et al. 2010; Frattini et al. 2010; Tsai et al. 2011; Komhoff et al. 2103; Gizicki et al. 2014; Fischer et al. 2014; Collison et al. 2015). The variant was absent from 105 controls and is reported at a frequency of 0.00173 in the European American population of the Exome Sequencing Project. Individuals who carry the p.Arg91LysfsTer14 variant in a homozygous state tend to have an earlier age of onset of the condition while the age of onset of disease when carried in the compound heterozygous state varies depending on the second variant (Morel et al. 2006). Functional studies in patient fibroblasts demonstrated that the p.Arg91LysfsTer variant results in significantly lower levels of transcript compared to wild type. Based on the potential impact of frameshift variants and the supporting evidence from the literature, the p.Arg91LysfsTer14 variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000001486 SCV000699394 pathogenic Methylmalonic acidemia with homocystinuria 2016-09-12 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.271dupA (p.Arg91Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 132/120196 control chromosomes at a frequency of 0.0010982, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant is a well known common disease variant and has been reported in numerous affected individuals in the literature, including individuals carrying the variant in the homozygous and compound heterozygous state (Lerner-Ellis_2006). Supporting the pathogenicity of this variant, incorporation of labelled methyltetrahydrofolate and propionate into cellular macromolecules was significantly affected in patients with homozygous or compound heterozygous c.271dupA (Lerner-Ellis_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000001486 SCV000640284 pathogenic Methylmalonic acidemia with homocystinuria 2018-07-02 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 2 of the MMACHC mRNA (c.271dupA), causing a frameshift at codon 91. This creates a premature translational stop signal (p.Arg91Lysfs*14) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic. This particular variant is a well known cause of early onset cobalamin C deficiency in the literature (PMID: 16311595, 19760748, 20631720, 24599607, 25894566). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000001486 SCV000223937 pathogenic Methylmalonic acidemia with homocystinuria 2014-12-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000001486 SCV000221198 pathogenic Methylmalonic acidemia with homocystinuria 2013-08-08 criteria provided, single submitter clinical testing The Arg91LysfsX14 variant in MMACHC has been identified in homozygosity in 81 individuals and in compound heterozygosity in 86 individuals with methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis 2006, Richard 2009, Liu 2010). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 91 and lead to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity.
OMIM RCV000001486 SCV000021641 pathogenic Methylmalonic acidemia with homocystinuria 2009-07-01 no assertion criteria provided literature only
OMIM RCV000585799 SCV000693726 pathogenic METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC 2018-09-27 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.