ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.64C>T (p.Arg22Ter) (rs765799472)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000203329 SCV000790666 pathogenic Methylmalonic aciduria cblA type 2017-04-04 criteria provided, single submitter clinical testing
GeneDx RCV000488986 SCV000577134 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing The R22X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (Yang et al., 2004, Richard et al., 2007; Merinero et al. 2008). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
GeneReviews RCV000203329 SCV000258469 pathogenic Methylmalonic aciduria cblA type 2016-01-07 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000590153 SCV000699976 pathogenic Methylmalonic acidemia 2017-06-19 criteria provided, single submitter clinical testing Variant summary: The MMAA c.64C>T (p.Arg22X) variant results in a premature termination codon, predicted to cause a truncated or absent MMAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and other laboratories in ClinVar (e.g. p.Arg145X, p.Gln248X, p.Arg330X, etc.). This variant was found in 5/215496 control chromosomes at a frequency of 0.0000232, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMAA variant (0.0018257). This variant has been reported in at least seven unrelated patients with methylmalonic acidemia in homozygous state as well in compound heterozygous state with other pathogenic/likely pathogenic variants (Yang_2004, Lerner-Ellis_2004, Merinero_2008, Dempsey-Nunez_2012, Nizon_2013, Manoli_2016). Biochemical analyses of the patient cells were consistent with severe impairment of enzymatic activity by this variant. A clinical diagnostic laboratory and a reputable database (via ClinVar) have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000203329 SCV000641768 pathogenic Methylmalonic aciduria cblA type 2017-06-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg22*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs765799472, ExAC 0.001%). This variant has been reported as homozygous or in combination with another MMAA variant in individuals affected with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15308131, 15523652, 17957493, 23026888, 26270765). Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). For these reasons, this variant has been classified as Pathogenic.

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