Submissions for variant NM_000255.4(MMUT):c.1420C>T (p.Arg474Ter)

gnomAD frequency: 0.00001  dbSNP: rs887126161

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670581	SCV000795450	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-11-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376565	SCV000963824	pathogenic	not provided	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg474*) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria (PMID: 15643616, 16281286). ClinVar contains an entry for this variant (Variation ID: 554873). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193332	SCV001362083	pathogenic	Methylmalonic acidemia	2019-12-20	criteria provided, single submitter	clinical testing	Variant summary: MUT c.1420C>T (p.Arg474X) 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 8e-06 in 251244 control chromosomes (gnomAD). c.1420C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (e.g. Acquaviva_2015, Forny_2016, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. Biochemical studies report low incorporation of propionate and low MUT enzyme activity for cells with the variant and assign mut0 class (Forny_2016, Worgan_2006). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798853	SCV005420784	pathogenic	Methylmalonic aciduria	2024-10-04	criteria provided, single submitter	research	PVS1,PM3(modearte),PM2
Natera, Inc.	RCV001271703	SCV001453051	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752988	SCV005360395	pathogenic	MMUT-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The MMUT c.1420C>T variant is predicted to result in premature protein termination (p.Arg474*). This variant has been reported in the homozygous state or heterozygous state with a second MMUT variant in individuals with methylmalonic acidemia, typically mmut0 type (Acquaviva et al. 2005. PubMed ID: 15643616; Worgan et al. 2006. PubMed ID: 16281286). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in MMUT are expected to be pathogenic. This variant is interpreted as pathogenic.