ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.387C>A (p.Tyr129Ter)

gnomAD frequency: 0.00003  dbSNP: rs796051992
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186011 SCV000238973 pathogenic not provided 2016-06-06 criteria provided, single submitter clinical testing The Y129X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was homozygous for the Y129X variant (Lerner-Ellis et al., 2004). This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay.
Counsyl RCV000671866 SCV000796896 pathogenic Methylmalonic aciduria, cblA type 2018-01-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000671866 SCV001582543 pathogenic Methylmalonic aciduria, cblA type 2024-01-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr129*) 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 (rs796051992, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25959030). ClinVar contains an entry for this variant (Variation ID: 203814). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420837 SCV001623231 pathogenic Methylmalonic acidemia 2021-05-09 criteria provided, single submitter clinical testing Variant summary: MMAA c.387C>A (p.Tyr129X) 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. The variant allele was found at a frequency of 8e-06 in 250652 control chromosomes. c.387C>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Lerner-Ellis_2004, Horster_2021). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000671866 SCV003821651 pathogenic Methylmalonic aciduria, cblA type 2023-01-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003401020 SCV004119870 pathogenic MMAA-related disorder 2023-01-23 criteria provided, single submitter clinical testing The MMAA c.387C>A variant is predicted to result in premature protein termination (p.Tyr129*). This variant has been reported, in the homozygous state or heterozygous state with a second causative MMAA variant, in at least two cblA type methylmalonic acidemia patients (MMA) (Lerner-Ellis et al 2004. PubMed ID: 15523652; Table S1 - Manoli et al. 2016. PubMed ID: 26270765; Hörster et al. 2020. PubMed ID: 32754920). Other loss-of-function variants surrounding this region have also been reported to be causative for MMA. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560678-C-A). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.
Baylor Genetics RCV000671866 SCV004193098 pathogenic Methylmalonic aciduria, cblA type 2023-12-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000671866 SCV005662966 pathogenic Methylmalonic aciduria, cblA type 2024-05-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000671866 SCV001452008 pathogenic Methylmalonic aciduria, cblA type 2020-09-16 no assertion criteria provided clinical testing

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