ClinVar Miner

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

gnomAD frequency: 0.00093  dbSNP: rs398124292
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Total submissions: 35
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham 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 2020-01-17 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24599607, 19760748, 25687216, 32164588, 31681265, 24210589, 20631720, 23954310, 23837176, 21228398, 16311595, 25894566, 26979128, 27014578, 29302025, 26990548, 30712249, 29294253, 28835862, 31137025, 28481040, 27252276, 31497484, 31574870, 32071835, 31503356, 30157807, 31998365, 31980526, 31589614, 32943488, 33587123)
Eurofins NTD LLC (GA) RCV000081737 SCV000331024 pathogenic not provided 2015-07-27 criteria provided, single submitter clinical testing
Illumina Laboratory Services,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 2021-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg91Lysfs*14) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs543840147, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with early onset cobalamin C deficiency (PMID: 16311595, 19760748, 20631720, 24599607, 25894566). ClinVar contains an entry for this variant (Variation ID: 1421). 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 2021-12-20 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous with NM_015506.3:c.658_660del._x000D_ Criteria applied: PVS1, PM3_VSTR, PP4
Institute of Human Genetics, Klinikum rechts der Isar RCV000001486 SCV001429930 pathogenic Cobalamin C disease 2020-06-05 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000081737 SCV001501894 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit,IRCCS Fondazione Stella Maris RCV000001486 SCV001519157 pathogenic Cobalamin C disease 2021-01-04 criteria provided, single submitter research
Genome-Nilou 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
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000081737 SCV002051724 pathogenic not provided 2021-01-28 criteria provided, single submitter clinical testing PVS1, PS3, PM3
New York Genome Center RCV000001486 SCV002097674 pathogenic Cobalamin C disease 2020-07-10 criteria provided, single submitter clinical testing
DASA RCV000001486 SCV002107079 pathogenic Cobalamin C disease 2022-03-05 criteria provided, single submitter clinical testing The c.270_271insA;p.(Arg91Lysfs*14) is a null frameshift variant (NMD) in the MMACHC gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1421; PMID: 16311595; PMID: 19760748; PMID: 20631720; PMID: 24599607; PMID: 25894566) - PS4. The variant is present at low allele frequencies population databases (rs398124292 – gnomAD 0.00008037%; ABraOM 0.003843 frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251853 SCV002522975 pathogenic See cases 2022-01-06 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PS4, PM3
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 2015-01-01 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
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
Clinical Genetics, Academic Medical Center RCV000081737 SCV001919692 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000081737 SCV001954166 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000081737 SCV001965896 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000001486 SCV002017508 pathogenic Cobalamin C disease 2021-01-22 no assertion criteria provided clinical testing

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