Submissions for variant NM_000255.4(MMUT):c.753+2T>A

dbSNP: rs796052006

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672182	SCV000797262	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781610	SCV000919782	pathogenic	Methylmalonic acidemia	2018-03-11	criteria provided, single submitter	clinical testing	Variant summary: MUT c.753+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. c.753+2T>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia. 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 in a patient with a compound heterozygote genotype of 753+2T>A/2206C>T. The most pronounced variant effect results in a Methylmalonyl-CoA mutase activity with (+AdoCbl, 50 M) and without AdoCbl (-AdoCbl) in crude homogenates of patient fibroblasts of -AdoCbl: 50 (control: 1058 +/- 381) and +AdoCbl: 199 (control: 2569 +/- 782) respectively. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000781610	SCV001652997	pathogenic	Methylmalonic acidemia	2020-06-05	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV001852417	SCV002124689	pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the MUT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs796052006, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with methylmalonic acidemia (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 203856). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000672182	SCV002808729	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-04-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000672182	SCV003819552	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-06-15	criteria provided, single submitter	clinical testing