ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.283C>T (p.Gln95Ter)

gnomAD frequency: 0.00001  dbSNP: rs104893846
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003308 SCV000793358 pathogenic Methylmalonic aciduria, cblA type 2017-08-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000003308 SCV001419137 pathogenic Methylmalonic aciduria, cblA type 2023-11-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln95*) 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 (rs104893846, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15523652). ClinVar contains an entry for this variant (Variation ID: 3158). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155012 SCV003844517 pathogenic Methylmalonic acidemia 2023-02-10 criteria provided, single submitter clinical testing Variant summary: MMAA c.283C>T (p.Gln95X) 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 9.2e-05 in 251242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (9.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.283C>T has been reported in the literature as a homozygous and compound heterozygous state in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017, Dobson_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
Baylor Genetics RCV000003308 SCV004193119 pathogenic Methylmalonic aciduria, cblA type 2023-01-25 criteria provided, single submitter clinical testing
OMIM RCV000003308 SCV000023466 pathogenic Methylmalonic aciduria, cblA type 2002-11-26 no assertion criteria provided literature only
GeneReviews RCV000003308 SCV000258472 not provided Methylmalonic aciduria, cblA type no assertion provided literature only
Natera, Inc. RCV000003308 SCV002084820 pathogenic Methylmalonic aciduria, cblA type 2021-05-04 no assertion criteria provided clinical testing

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