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

gnomAD frequency: 0.00003  dbSNP: rs200596762

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186056	SCV000239020	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Reported previously in patients with methylmalonic acidemia (MMA) in the homozygous state or with a second variant in the MUT gene (Acquaviva et al., 2005; Chu et al., 2016; Rosa et al., 2018); 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: 19375370, 17957493, 35361390, 25525159, 23045948, 21671183, 16281286, 27233228, 29881561, 26790480, 17470278, 15781192, 25689098, 31525265, 31622506, 15643616, 32778825, 32754920, 27535533)
Counsyl	RCV000666877	SCV000791244	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-05-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Invitae	RCV000186056	SCV001579209	pathogenic	not provided	2022-10-31	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. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs200596762, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with MUT-related conditions (PMID: 15643616, 15781192, 27233228). ClinVar contains an entry for this variant (Variation ID: 203855). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000666877	SCV003807049	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-07-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated
3billion	RCV000666877	SCV003841455	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000203855 / PMID: 15643616). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc.	RCV001271714	SCV001453062	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing