Total submissions: 35
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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 |
RCV000081737 | SCV000331024 | pathogenic | not provided | 2015-07-27 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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, |
RCV000081737 | SCV000511400 | pathogenic | not provided | 2016-07-13 | criteria provided, single submitter | clinical testing | |
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, |
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, |
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, |
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, |
RCV000001486 | SCV001424277 | pathogenic | Cobalamin C disease | 2020-04-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
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, |
RCV000001486 | SCV001429930 | pathogenic | Cobalamin C disease | 2020-06-05 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000081737 | SCV001501894 | pathogenic | not provided | 2021-11-01 | criteria provided, single submitter | clinical testing | |
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, |
RCV000001486 | SCV001519157 | pathogenic | Cobalamin C disease | 2021-01-04 | criteria provided, single submitter | research | |
Genome- |
RCV000001486 | SCV001652720 | pathogenic | Cobalamin C disease | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000081737 | SCV001713012 | pathogenic | not provided | 2020-12-22 | criteria provided, single submitter | clinical testing | PVS1, PS3, PS4, PM3, PP4 |
Fulgent Genetics, |
RCV000001486 | SCV001752587 | pathogenic | Cobalamin C disease | 2021-06-30 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
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, |
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, |
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, |
RCV000001486 | SCV001423145 | pathogenic | Cobalamin C disease | 2020-04-23 | no assertion criteria provided | research | |
Sydney Genome Diagnostics, |
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, |
RCV001273215 | SCV001456007 | pathogenic | Methylmalonic acidemia with homocystinuria cblC | 2020-09-16 | no assertion criteria provided | clinical testing | |
Laboratory of Diagnostic Genome Analysis, |
RCV000081737 | SCV001799510 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000081737 | SCV001919692 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000081737 | SCV001954166 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000081737 | SCV001965896 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Perkin |
RCV000001486 | SCV002017508 | pathogenic | Cobalamin C disease | 2021-01-22 | no assertion criteria provided | clinical testing |