ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2179C>T (p.Arg727Ter) (rs779990936)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725155 SCV000334536 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Invitae RCV000203410 SCV000641778 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MUT gene (p.Arg727*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 24 amino acids of the MUT protein. This variant is present in population databases (rs779990936, ExAC 0.01%). This variant has been reported as homozygous or in combination with another MUT variant in multiple individuals affected with methylmalonic acidemia (PMID: 16281286, 17445044, 22727635, 17075691, 26454439, 27489777). ClinVar contains an entry for this variant (Variation ID: 218998). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000203410 SCV000792964 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-07-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193329 SCV001362080 pathogenic Methylmalonic acidemia 2019-08-15 criteria provided, single submitter clinical testing Variant summary: MUT c.2179C>T (p.Arg727X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251350 control chromosomes (gnomAD). c.2179C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Sakamoto_2007, Chu_2016). 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. Four ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725155 SCV001371442 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
GeneReviews RCV000203410 SCV000258514 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-12-01 no assertion criteria provided literature only mut(0) enzymatic subtype when homozygous

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