Submissions for variant NM_172250.3(MMAA):c.450dup (p.Pro151fs)

dbSNP: rs754973022

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666170	SCV000790417	pathogenic	Methylmalonic aciduria, cblA type	2017-03-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193916	SCV001363090	pathogenic	Methylmalonic acidemia	2019-02-13	criteria provided, single submitter	clinical testing	Variant summary: The variant, MMAA c.450dupG (p.Pro151AlafsX19) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.593_596delCTGA(p.Thr198fsX6)). The variant allele was found at a frequency of 1.2e-05 in 246322 control chromosomes and has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Hauser_2011, Martinez_2005, OShea_2012, and Plessl_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Lerner-Ellis_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000666170	SCV001372795	pathogenic	Methylmalonic aciduria, cblA type	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro151Alafs*19) 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). This variant is present in population databases (rs754973022, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 20549364). ClinVar contains an entry for this variant (Variation ID: 551182). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002245082	SCV002513098	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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: 21048060, 22614770, 28497574, 15523652, 20549364)
Baylor Genetics	RCV000666170	SCV004193082	pathogenic	Methylmalonic aciduria, cblA type	2023-10-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000666170	SCV002084823	pathogenic	Methylmalonic aciduria, cblA type	2020-11-25	no assertion criteria provided	clinical testing