ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.450dup (p.Pro151fs) (rs754973022)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666170 SCV000790417 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblA 2017-03-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193916 SCV001363090 pathogenic Methylmalonic acidemia 2019-02-13 criteria provided, single submitter clinical testing Variant summary: The variant, MMAA c.450dupG (p.Pro151AlafsX19) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.593_596delCTGA(p.Thr198fsX6)). The variant allele was found at a frequency of 1.2e-05 in 246322 control chromosomes and has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Hauser_2011, Martinez_2005, OShea_2012, and Plessl_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Lerner-Ellis_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000666170 SCV001372795 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblA 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro151Alafs*19) in the MMAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs754973022, ExAC 0.003%). This variant has been observed in several individuals affected with methylmalonic aciduria cobalamin A type (PMID: 15523652, 20549364). ClinVar contains an entry for this variant (Variation ID: 551182). 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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