ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.615C>A (p.Tyr205Ter)

gnomAD frequency: 0.00003  dbSNP: rs747527726
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674536 SCV000799888 pathogenic Cobalamin C disease 2018-05-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674536 SCV000958795 pathogenic Cobalamin C disease 2024-02-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr205*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the MMACHC protein. This variant is present in population databases (no rsID available, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with combined methylmalonic aciduria and homocystinuria (PMID: 16311595, 19914430, 20631720, 25388550). ClinVar contains an entry for this variant (Variation ID: 558292). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000674536 SCV001162919 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674536 SCV002015072 pathogenic Cobalamin C disease 2021-10-25 criteria provided, single submitter clinical testing Variant summary: MMACHC c.615C>A (p.Tyr205X) 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 was absent in 249538 control chromosomes. c.615C>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria, e.g. Hu_2018, Zhang_2020). These data indicate that the variant may 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.
Genome-Nilou Lab RCV000674536 SCV004178210 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000674536 SCV005417440 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics RCV000674536 SCV005654948 pathogenic Cobalamin C disease 2024-06-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV001275216 SCV001460140 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing

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