ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 26
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000001486 SCV000221198 pathogenic Cobalamin C disease 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.
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081737 SCV000331024 pathogenic not provided 2015-07-27 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.
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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507720 SCV000604238 pathogenic not specified 2016-09-05 criteria provided, single submitter clinical testing
Invitae RCV000001486 SCV000640284 pathogenic Cobalamin C disease 2020-10-31 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001486 SCV000699394 pathogenic Cobalamin C disease 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000001486 SCV000923540 uncertain significance Cobalamin C disease 2019-01-01 criteria provided, single submitter clinical testing
Mendelics RCV000001486 SCV001135276 pathogenic Cobalamin C disease 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000001486 SCV001162896 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000001486 SCV001194113 pathogenic Cobalamin C disease 2019-12-20 criteria provided, single submitter clinical testing NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is classified as pathogenic in the context of cblC type methylmalonic aciduria and homocystinuria and may be associated with the early onset form of disease. Sources cited for classification include the following: PMID 19370762. Classification of NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Elsea Laboratory,Baylor College of Medicine RCV000001486 SCV001424277 pathogenic Cobalamin C disease 2020-04-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000001486 SCV001428796 pathogenic Cobalamin C disease 2019-05-24 criteria provided, single submitter clinical testing This variant was identified as homozygous
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081737 SCV001501894 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000001486 SCV001652720 pathogenic Cobalamin C disease 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000081737 SCV001713012 pathogenic not provided 2020-12-22 criteria provided, single submitter clinical testing PVS1, PS3, PS4, PM3, PP4
Fulgent Genetics,Fulgent Genetics RCV000001486 SCV001752587 pathogenic Cobalamin C disease 2021-06-30 criteria provided, single submitter clinical testing
OMIM RCV000001486 SCV000021641 pathogenic Cobalamin C disease 2009-07-01 no assertion criteria provided literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000001486 SCV000223937 pathogenic Cobalamin C disease 2014-12-15 no assertion criteria provided clinical testing
OMIM RCV000585799 SCV000693726 pathogenic METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC 2018-09-27 no assertion criteria provided literature only
Neurology Department,Peking University First Hospital RCV000001486 SCV001423145 pathogenic Cobalamin C disease 2020-04-23 no assertion criteria provided research
Institute of Human Genetics, Klinikum rechts der Isar RCV000001486 SCV001429930 pathogenic Cobalamin C disease 2020-06-05 no assertion criteria provided clinical testing
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328208 SCV001449357 pathogenic Atypical hemolytic uremic syndrome 2019-05-09 no assertion criteria provided clinical testing This individual is heterozygous for a pathogenic variant c.271dup in the MMACHC gene. This frameshifting variant is predicted to create a premature stop codon p.(Arg91Lysfs*14) and may result in a null allele due to nonsense-mediated mRNA decay. This variant is one of the most common variants associated with cblC type methylmalonic aciduria and homocystinuria (Lerner-Ellis et al 2006 Nat Genet 38:93-100). This variant is considered to be pathogenic according to the ACMG guidelines.
Natera, Inc. RCV001273215 SCV001456007 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000081737 SCV001799510 pathogenic not provided no assertion criteria provided clinical testing

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.