ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1677-1G>A (rs754369323)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664627 SCV000788623 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-21 criteria provided, single submitter clinical testing
Invitae RCV000664627 SCV000934490 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-08-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the MUT 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 (rs754369323, ExAC 0.01%). This variant has been observed in individuals affected with methylmalonic acidemia (PMID: 16281286, 26454439, 17113806, 23430940). 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 MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193330 SCV001362081 pathogenic Methylmalonic acidemia 2019-12-15 criteria provided, single submitter clinical testing Variant summary: MUT c.1677-1G>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: Four predict the variant abolishes the canonical 3' acceptor site. Two predict the variant strengthens an alternate cryptic intronic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251050 control chromosomes. c.1677-1G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (example, Worgan_2006, Lempp_2007, Liu_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
SingHealth Duke-NUS Institute of Precision Medicine RCV000664627 SCV000853113 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-06-07 no assertion criteria provided curation

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