ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1560+1G>T (rs200019422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669261 SCV000793996 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-09-06 criteria provided, single submitter clinical testing
Invitae RCV000669261 SCV000932331 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-08-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the MUT 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 combination with another MUT variant in several individuals affected with methylmalonic aciduria (PMID: 15643616, 17075691). 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 RCV001193326 SCV001362077 pathogenic Methylmalonic acidemia 2019-06-13 criteria provided, single submitter clinical testing Variant summary: MUT c.1560+1G>T 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. 5/5 computational tools predict the variant abolishes a 5 prime splicing donor site and a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247968 control chromosomes (gnomAD). The variant, c.1560+1G>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Cavicchi_2005, Acquaviva_2005, Sakamoto_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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