ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1022dup (p.Asn341fs) (rs752898811)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669504 SCV000794261 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-10-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780494 SCV000917795 pathogenic Methylmalonic acidemia 2018-11-16 criteria provided, single submitter clinical testing Variant summary: MUT c.1022dupA (p.Asn341LysfsX20) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Arg467X, p.Arg511X). The variant allele was found at a frequency of 1.6e-05 in 246050 control chromosomes. c.1022dupA has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Forny_2016, Martinez_2005, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000669504 SCV000947111 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn341Lysfs*20) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752898811, ExAC 0.02%). This variant has been observed in combination with another MUT variant in several individuals affected with methylmalonic acidemia (PMID: 16281286, 27167370). ClinVar contains an entry for this variant (Variation ID: 553958). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.

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