Submissions for variant NM_000255.4(MMUT):c.1207C>T (p.Arg403Ter) (rs727504020)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000790701	SCV000231500	pathogenic	not provided	2013-12-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000179277	SCV000245636	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2014-12-22	criteria provided, single submitter	clinical testing	The p.Arg403X variant in MUT has been reported in 1 individual with clinical features of methylmalonic acidemia and no enzyme activity, though a second allele was not identified (Peters 2002). This variant has also been identified in 1/67564 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Animal models in mice have shown that this variant causes features of the disease (Buck 2012). This nonsense variant leads to a premature termination codon at position 403, which is predicted to lead to a truncated or absent protein. Homozygous or compound heterozygous loss of function of MUT has been shown to cause methylmalonic acidemia. In summary, this variant meets our criteria to be classified as pathogenic for methylmalonic acidemia in an autosomal recessive manner.
Counsyl	RCV000179277	SCV000789777	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-02-17	criteria provided, single submitter	clinical testing
Invitae	RCV000179277	SCV000959453	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2019-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg403*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727504020, ExAC 0.001%). This variant has been observed in several individuals and families affected with MUT-related conditions (PMID: 12402345, 27167370, 26790480, 27233228, 17113806). ClinVar contains an entry for this variant (Variation ID: 167310). 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	RCV001193927	SCV001363102	pathogenic	Methylmalonic acidemia	2019-12-26	criteria provided, single submitter	clinical testing	Variant summary: MUT c.1207C>T (p.Arg403X) 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. The variant allele was found at a frequency of 4e-05 in 251338 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (4e-05 vs 0.0024). c.1207C>T has been reported in the literature in several individuals affected with Methylmalonic Acidemia (e.g. Worgan_2006, Forny_2016). These data indicate that the variant is very likely to be associated with disease. These studies also reported experimental evidence evaluating an impact on protein function, and demonstrated the variant results in <10% of normal activity (Worgan_2006, Forny_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.