ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1956+2T>C (rs750619189)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664805 SCV000788820 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-01-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000664805 SCV000893720 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000664805 SCV000916150 uncertain significance Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-11-06 criteria provided, single submitter clinical testing This variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae RCV000664805 SCV001236194 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 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 (rs750619189, ExAC 0.07%). This variant has not been reported in the literature in individuals with MUT-related conditions. ClinVar contains an entry for this variant (Variation ID: 550143). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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