Submissions for variant NM_172250.3(MMAA):c.586C>T (p.Arg196Ter)

gnomAD frequency: 0.00001  dbSNP: rs1029096863

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000545383	SCV000641767	pathogenic	Methylmalonic aciduria, cblA type	2023-08-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 466217). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 21545677, 23711287, 25636100; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg196*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193915	SCV001363089	pathogenic	Methylmalonic acidemia	2019-04-08	criteria provided, single submitter	clinical testing	Variant summary: MMAA c.586C>T (p.Arg196X) 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 8.1e-06 in 246142 control chromosomes (gnomAD). c.586C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (Plessl_2017, Sun_2015, Lubrano_2013, Nizon_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000545383	SCV001554461	pathogenic	Methylmalonic aciduria, cblA type	2021-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001584283	SCV001813964	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27629047, 29996803, 34670123, 25567501, 23711287, 25636100, 16247646, 31622506, 33726816, 32754920, 33453710, 21545677)
Baylor Genetics	RCV000545383	SCV004193093	pathogenic	Methylmalonic aciduria, cblA type	2023-10-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000545383	SCV004805029	pathogenic	Methylmalonic aciduria, cblA type	2024-03-17	criteria provided, single submitter	research
Counsyl	RCV000545383	SCV000793859	pathogenic	Methylmalonic aciduria, cblA type	2017-09-01	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000545383	SCV001190759	pathogenic	Methylmalonic aciduria, cblA type	2020-02-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000545383	SCV001452010	pathogenic	Methylmalonic aciduria, cblA type	2020-09-16	no assertion criteria provided	clinical testing