Submissions for variant NM_000255.4(MMUT):c.682C>T (p.Arg228Ter) (rs200596762)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186056	SCV000239020	pathogenic	not provided	2017-06-22	criteria provided, single submitter	clinical testing	The R228X nonsense variant has been reported previously in association with methylmalonic acidemia (MMA) (Acquaviva et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R228X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, R228X is interpreted to be pathogenic.
Counsyl	RCV000666877	SCV000791244	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-05-15	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000666877	SCV000916152	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-09-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the MUT c.682C>T (p.Arg228Ter) variant has been identified in a homozygous state in at least one proband and in a compound heterozygous state in at least eleven probands with methylmalonic academia (Acquaviva et al. 2005; Chu et al. 2016; Harrington et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000209 in the Latino population of the Genome Aggregation Database. Based on the evidence and the potential impact of stop-gained variants, the p.Arg228Ter 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	RCV000666877	SCV000960345	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg228*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200596762, ExAC 0.003%). This variant has been observed in several individuals affected with MUT-related conditions (PMID: 15643616, 15781192, 27233228). ClinVar contains an entry for this variant (Variation ID: 203855). 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	RCV001192657	SCV001360916	pathogenic	Methylmalonic acidemia	2019-05-02	criteria provided, single submitter	clinical testing	Variant summary: MUT c.682C>T (p.Arg228X) 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 6.4e-05 in 250348 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (6.4e-05 vs 0.0024). c.682C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Harrington_2016, Acquaviva_2005). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.