ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.197-1G>T (rs763935916)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590462 SCV000699779 pathogenic Methylmalonic acidemia 2016-07-08 criteria provided, single submitter clinical testing Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000203326 SCV001149836 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2018-11-16 criteria provided, single submitter clinical testing
Invitae RCV000203326 SCV001400676 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2019-08-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs763935916, ExAC 0.02%). This variant has been observed in several individuals affected with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000203326 SCV000258532 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2016-01-07 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000203326 SCV000579473 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB no assertion criteria provided clinical testing The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster.
Counsyl RCV000203326 SCV000797038 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2018-01-09 no assertion criteria provided clinical testing

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