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

Total submissions: 13

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