ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.82-1G>A (rs1255179780)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672739 SCV000797875 likely pathogenic Methylmalonic acidemia with homocystinuria 2018-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000672739 SCV000917673 likely pathogenic Methylmalonic acidemia with homocystinuria 2018-12-10 criteria provided, single submitter clinical testing Variant summary: MMACHC c.82-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245794 control chromosomes (gnomAD). c.82-1G>A has been reported in the literature in homozygote and compound heterozygote individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (Huemer_2014, Lerner-Ellis_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000672739 SCV000941013 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the MMACHC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with MMACHC-related conditions (PMID: 19370762, 25398587). ClinVar contains an entry for this variant (Variation ID: 556698). 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 MMACHC are known to be pathogenic (PMID: 16311595). For these reasons, this variant has been classified as Pathogenic.

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