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

gnomAD frequency: 0.00093  dbSNP: rs398124292

Total submissions: 35

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