ClinVar Miner

Submissions for variant NM_015506.2(MMACHC):c.482G>A (rs121918243)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000081740 SCV000604240 pathogenic not provided 2017-07-25 criteria provided, single submitter clinical testing The MMACHC c.482G>A, p.Arg161Gln variant (rs121918243) has been previously reported in individuals with late onset methylmalonic aciduria and homocystinuria, cblC type (Bodamer 2001, Collison 2015, Lerner-Ellis 2009, Liu 2010, Morel 2006, Rhamander 2014, Tsai 2007, Wang 2012). Functional characterization of the variant protein indicates lower thermostability compared to wild type and impaired binding and stabilization of vitamin B12 (Froese 2010, Gherasim 2015). The variant is listed as pathogenic in ClinVar (Variation ID: 1425), and observed in the general population databases at a frequency of 0.008 percent in the Exome Variant Server (1/12374 alleles), and 0.015 percent in the Genome Aggregation Database (41/277058 alleles). The arginine at residue 161 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic.
Ambry Genetics RCV000624532 SCV000742800 pathogenic Inborn genetic diseases 2016-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081740 SCV000610534 pathogenic not provided 2017-08-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081740 SCV000331269 pathogenic not provided 2012-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000081740 SCV000321902 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing The R161Q pathogenic variant in the MMACHC gene has been previously reported in association with methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis et al., 2006; Wang et al., 2012; Tsai et al., 2007). This variant has been associated with a rare late-onset disease course with symptoms that resolved with hydroxycobalamin treatment (Wang et al., 2012). Functional studies found that R161Q is associated with reduced protein stability and dealkylation compared to wild type, and had reduced binding affinity to cyanocobalamin (Gherasim et al., 2015; Froese et al., 2009). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret R161Q to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000001490 SCV000699401 pathogenic Methylmalonic acidemia with homocystinuria 2017-05-11 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.482G>A (p.Arg161Gln) variant causes a missense change involving the alteration of a highly conserved nucleotide. The variant alters a cobalamin binding site on conserved domain MMACHC-like (PM1). 3/4 in silico tools predict deleterious outcome for this variant (SNP&GO was not used due to a low reliability index). In the functional studies mutant R161Q has a decreased ability to bind incoming CNCbl, which results in a decreased ability to reductively decyanate the CNCbl to the cob(II)alamin form used in the metabolic pathway (PS3). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.000195 (18/120402 chrs tested), predominantly in individuals of Latino descent (0.0013; 15/16508chrs tesed). The observed frequencies are extremely low and do not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (~0.0031) (PM2). The c.482G>A was identified heterozygously in an infant with combined methylmalonic aciduria and homocystinuria without availability of segregation data and parental clinical information; this patient also tested positive for a known pathogenic mutation in the same gene (phase is unknown). The variant of interest was reported in compound heterozygosity in multiple affected individuals presenting with biochemically confirmed dx of late-onset methylmalonic aciduria and homocystinuria and proven segregation within the family (PM3, PP1, PP4). At least one case of early-onset presentation has been reported in 2.5 months old infant homozygous for the variant of interest. The codon Arg161 appears to be a mutational hot spot, as other alteration of the same codon, c.481C>G (p.Arg161Gly) (PM5) and c.481C>T (p.Arg161*) were identified in patients with methylmalonic aciduria and homocystinuria. In addition, a clinical diagnostic laboratory/reputable database classified this variant as Pathogenic (PP5). Considering all evidence and ACMG guidelines, the variant was classified as Pathogenic.
Invitae RCV000001490 SCV000762779 pathogenic Methylmalonic acidemia with homocystinuria 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 161 of the MMACHC protein (p.Arg161Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121918243, ExAC 0.1%). This variant has been observed in multiple in individuals and has been reported to segregate in families with late-onset methylmalonic aciduria and homocystinuria (PMID: 16311595, 22560872, 26283149, 25687216, 28218226, 17853453, 19370762, 21055272). ClinVar contains an entry for this variant (Variation ID: 1425). Experimental studies have shown that this missense change impairs MMACHC protein stability and enzyme activity (PMID: 19700356, 25809485, 20219402, 20219402). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001490 SCV000021645 pathogenic Methylmalonic acidemia with homocystinuria 2010-09-01 no assertion criteria provided literature only
SingHealth Duke-NUS Institute of Precision Medicine RCV000721969 SCV000853112 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-06-07 no assertion criteria provided curation

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