Submissions for variant NM_172250.3(MMAA):c.988C>T (p.Arg330Ter)

gnomAD frequency: 0.00001  dbSNP: rs571038432

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186014	SCV000238976	pathogenic	not provided	2015-04-20	criteria provided, single submitter	clinical testing	p.Arg330Ter (CGA>TGA): c.988 C>T in exon 7 of the MMAA gene (NM_172250.2). The R330X nonsense mutation in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was homozygous for the R330X mutation (Lerner-Ellis et al., 2004). This mutation is predicted to cause loss of normal protein function through protein truncation. The variant is found in MMA-MET panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193917	SCV001363091	pathogenic	Methylmalonic acidemia	2019-12-12	criteria provided, single submitter	clinical testing	Variant summary: MMAA c.988C>T (p.Arg330X) 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 8e-06 in 251296 control chromosomes (gnomAD). c.988C>T has been reported in the literature in individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203343	SCV002238937	pathogenic	Methylmalonic aciduria, cblA type	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg330*) in the MMAA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the MMAA protein. This variant is present in population databases (rs571038432, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with cobalamin A type methylmalonic aciduria (PMID: 15523652, 28497574). ClinVar contains an entry for this variant (Variation ID: 203816). This variant disrupts a region of the MMAA protein in which other variant(s) (p.Arg359*) have been determined to be pathogenic (PMID: 23026888; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000203343	SCV004193125	pathogenic	Methylmalonic aciduria, cblA type	2024-01-05	criteria provided, single submitter	clinical testing
GeneReviews	RCV000203343	SCV000258481	not provided	Methylmalonic aciduria, cblA type		no assertion provided	literature only