ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.420G>A (p.Trp140Ter)

gnomAD frequency: 0.00001  dbSNP: rs796051996
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000190393 SCV000818736 pathogenic Cobalamin C disease 2023-11-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp140*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 143 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs796051996, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595). ClinVar contains an entry for this variant (Variation ID: 203827). This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Trp203*) have been determined to be pathogenic (PMID: 16311595, 23954310, 25772322). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000190393 SCV001372270 pathogenic Cobalamin C disease 2020-06-28 criteria provided, single submitter clinical testing Variant summary: MMACHC c.420G>A (p.Trp140X) 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 4e-06 in 249328 control chromosomes. c.420G>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) and subsequently cited by others (example Lerner-Ellis_2006, Lerner-Ellis_2009, Froese_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
Genome-Nilou Lab RCV000190393 SCV004178169 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000190393 SCV004193191 pathogenic Cobalamin C disease 2024-02-29 criteria provided, single submitter clinical testing
Inserm U 954, Faculté de Médecine de Nancy RCV000190393 SCV000243927 not provided Cobalamin C disease no assertion provided not provided

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