ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.742C>T (p.Gln248Ter)

gnomAD frequency: 0.00001  dbSNP: rs757548934
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586897 SCV000699977 pathogenic Methylmalonic acidemia 2016-12-30 criteria provided, single submitter clinical testing Variant summary: The MMAA c.742C>T (p.Gln248X) variant results in a premature termination codon, predicted to cause a truncated or absent MMAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The truncated protein is expected to remove the 170 amino acids in the C-terminus, which includes part of the P-loop containing nucleoside triphosphate hydrolase domain. One in silico tool predicts a damaging outcome for this variant. Xiong_2015 predicted a large splicing change induced by this variant. However, this change was not predicted by 5/5 splice prediction tools. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4/121506 control chromosomes at a frequency of 0.0000329 (all alleles are from East Asian subpopuation), which does not exceed the estimated maximal expected allele frequency of a pathogenic MMAA variant (0.0018257). This variant has been reported in at least two patients. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001240486 SCV001413432 pathogenic Methylmalonic aciduria, cblA type 2023-08-14 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 496554). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25748407, 28497574). This variant is present in population databases (rs757548934, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln248*) 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).
Baylor Genetics RCV001240486 SCV004193101 pathogenic Methylmalonic aciduria, cblA type 2024-01-09 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001240486 SCV005662985 pathogenic Methylmalonic aciduria, cblA type 2024-06-24 criteria provided, single submitter clinical testing

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