Submissions for variant NM_000255.4(MMUT):c.670G>T (p.Glu224Ter) (rs1554160638)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668034	SCV000792577	likely pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-07-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000760390	SCV000890261	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing	The E224X variant has been reported previously in an individual with mut0 MMA who also had a second nonsense variant identified in the MUT gene (Worgan et al., 2006). The E224X variant is not observed in large population cohorts (Lek et al., 2016). This E224X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret E224X as pathogenic.
Invitae	RCV000668034	SCV001223502	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2019-03-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu224*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with methylmalonic aciduria (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 552718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.