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

gnomAD frequency: 0.00005  dbSNP: rs727504020

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790701	SCV000231500	pathogenic	not provided	2013-12-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790701	SCV000959453	pathogenic	not provided	2025-01-19	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. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs727504020, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with MUT-related conditions (PMID: 12402345, 17113806, 26790480, 27167370, 27233228). ClinVar contains an entry for this variant (Variation ID: 167310). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CeGaT Center for Human Genetics Tuebingen	RCV000790701	SCV002062679	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000790701	SCV002577231	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	A mouse model carrying the equivalent variant, in the homozygous state, in murine MUT had features which mimicked human methylmalonic acidemia (Buck et al., 2012).; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17113806, 26790480, 27233228, 23024777, 25525159, 12402345, 27167370, 31622506, 35361390, 33413471)
Fulgent Genetics, Fulgent Genetics	RCV000179277	SCV002776508	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-03-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271707	SCV001453055	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing