Submissions for variant NM_000255.4(MMUT):c.1399C>T (p.Arg467Ter)

gnomAD frequency: 0.00003  dbSNP: rs774159791

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587544	SCV000696305	pathogenic	Methylmalonic acidemia	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The MUT c.1399C>T variant results into nonsense mutation in exon 7 predicted to cause a loss of protein function due to production of a truncated protein or nonsense-mediated mRNA decay. It was exclusively observed in the Non-Finnish European sub-cohort of the ExAC project at an allele frequency of 0.0015%, which does not exceed the maximal expected allele frequency of a disease-causing MUT allele (0.24%). In the literature, the variant was observed in several patients with methylmalonic aciduria in compound heterozygosity with other truncating as well as missense variants, consistent with a disease-causing nature. Two reputable databases as well as one clinical lab has classified this variant as pathogenic. Considering all evidence, the variant has been classified as a Disease Variant/Pathogenic.
Illumina Laboratory Services, Illumina	RCV000664980	SCV000916151	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-10-05	criteria provided, single submitter	clinical testing	The MUT c.1399C>T (p.Arg467Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been described in five studies in eight probands with classic methylmalonic acidemia (MMA), with one in a homozygous state and seven in a compound heterozygous state (Peters et al. 2002; Acquaviva et al. 2005; Worgan et al. 2006; Dündar et al. 2012; Liu et al. 2012). The p.Arg467Ter variant was absent from 48 anonymous controls and is reported at a frequency of 0.001320 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies showed that six of the patients (one homozygote and five compound heterozygotes) carrying the p.Arg467Ter variant demonstrated zero enzyme activity ('mut0' phenotype) (Acquaviva et al. 2005). Based on the potential impact of truncating variants and presence in affected individuals, the p.Arg467Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001381507	SCV001579939	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg467*) 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 (rs774159791, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 12402345, 16281286, 22727635, 26790480). ClinVar contains an entry for this variant (Variation ID: 495778). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000664980	SCV002810879	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2021-11-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000664980	SCV000789026	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-01-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001271704	SCV001453052	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing