ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs765799472
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000488986 SCV000577134 pathogenic not provided 2020-05-26 criteria provided, single submitter clinical testing Nonsense 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23026888, 15523652, 26270765, 15308131, 17957493, 17948227, 19375370)
Invitae RCV000203329 SCV000641768 pathogenic Methylmalonic aciduria, cblA type 2024-01-17 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. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs765799472, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria (PMID: 15308131, 15523652, 17957493, 23026888, 26270765). ClinVar contains an entry for this variant (Variation ID: 218969). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Counsyl RCV000203329 SCV000790666 pathogenic Methylmalonic aciduria, cblA type 2017-04-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000203329 SCV004193092 pathogenic Methylmalonic aciduria, cblA type 2023-10-06 criteria provided, single submitter clinical testing
GeneReviews RCV000203329 SCV000258469 not provided Methylmalonic aciduria, cblA type no assertion provided literature only
Natera, Inc. RCV000203329 SCV001452004 pathogenic Methylmalonic aciduria, cblA type 2020-09-16 no assertion criteria provided clinical testing

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