ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.586C>T (p.Arg196Ter) (rs1029096863)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545383 SCV000641767 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblA 2019-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 196 (p.Arg196*) of 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. This particular variant has been observed as homozygous or compound heterozygous in individuals affected with methylmalonic acidemia (PMID: 21545677, 25636100, 23711287, Invitae). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193915 SCV001363089 pathogenic Methylmalonic acidemia 2019-04-08 criteria provided, single submitter clinical testing Variant summary: MMAA c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246142 control chromosomes (gnomAD). c.586C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (Plessl_2017, Sun_2015, Lubrano_2013, Nizon_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000545383 SCV000793859 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblA 2017-09-01 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000545383 SCV001190759 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblA 2020-02-05 no assertion criteria provided clinical testing

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