ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.556C>T (p.Arg186Trp) (rs28941784)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186017 SCV000238979 pathogenic not provided 2015-07-17 criteria provided, single submitter clinical testing R186W in the MMAB gene has been reported previously in association with vitamin-B12 responsive methylmalonic acidemia (MMA) in a patient who presented with symptoms at day 7 of life (Lerner-Ellis et al., 2006). Mutation occurs in the active site of the MMAB enzyme (Lerner-Ellis et al., 2006). The variant is found in MMAB panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000003241 SCV000375743 pathogenic Methylmalonic aciduria cblB type 2017-04-28 criteria provided, single submitter clinical testing The MMAB c.556C>T (p. Arg186Trp) missense variant has been reported in six studies in which it is found in a total of 29 methylmalonic acidemia (MMA) patients, including 15 homozygotes, 13 compound heterozygotes, and one heterozygote in whom a second variant was not identified (Dobson et al. 2002; Lerner-Ellis et al. 2006; Hauser et al. 2011; O'Shea et al. 2012; Illson et al. 2013; Nizon et al. 2013). The variant was present in a heterozygous state in four of 120 non-cblB cell lines, absent from 100 control alleles, and is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies suggest that the p.Arg186Trp variant results in an unstable protein and disrupts affinity binding between MMAB and adenosylcobalamin (Zhang et al. 2006; Zhang et al. 2009). Based on the collective evidence, the p.Arg186Trp variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000296390 SCV000699780 pathogenic Methylmalonic acidemia 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The MMAB c.556C>T (p.Arg186Trp) variant located in the Adenosycobalamin biosnthesis domain (via InterPro) causes an alteration of a non-conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was found in 17/120070 control chromosomes at a frequency of 0.0001416, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMAB variant (0.0013944). Multiple publications cite the variant in affected individuals as homozygotes and compound heterozygotes and has been indicated to be a known common disease mutation (Lerner-Ellis_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000186017 SCV000854910 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Invitae RCV000003241 SCV000941899 pathogenic Methylmalonic aciduria cblB type 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 186 of the MMAB protein (p.Arg186Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs28941784, ExAC 0.02%). This variant has been observed in many individuals and families affected with MMAB-related conditions (PMID: 12471062, 16410054). ClinVar contains an entry for this variant (Variation ID: 3095). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID:19625202, 16439175). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003241 SCV000023399 pathogenic Methylmalonic aciduria cblB type 2002-12-15 no assertion criteria provided literature only
GeneReviews RCV000003241 SCV000258526 pathogenic Methylmalonic aciduria cblB type 2016-01-07 no assertion criteria provided literature only
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000003241 SCV000267127 pathogenic Methylmalonic aciduria cblB type 2014-06-15 no assertion criteria provided research
Counsyl RCV000003241 SCV000486615 pathogenic Methylmalonic aciduria cblB type 2016-11-03 no assertion criteria provided clinical testing

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