Submissions for variant NM_000255.4(MMUT):c.1194_1195TG[1] (p.Val399fs) (rs1227030642)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000701062	SCV000829844	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2019-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val399Glufs*24) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with methylmalonic acidemia (PMID: 16281286). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000701062	SCV001137133	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001174604	SCV001337798	pathogenic	Methylmalonic acidemia	2020-01-21	criteria provided, single submitter	clinical testing	Variant summary: MUT c.1196_1197delTG (p.Val399GlufsX24) 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. The variant allele was found at a frequency of 4e-06 in 251324 control chromosomes (gnomAD). c.1196_1197delTG has been reported in the literature in one homozygous individual affected with Methylmalonic Acidemia (Worgan_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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