Submissions for variant NM_000255.4(MMUT):c.1025C>A (p.Ser342Ter) (rs770466993)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665393	SCV000789509	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-02-03	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000587657	SCV000696302	pathogenic	Methylmalonic acidemia	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The MUT c.1025C>A (p.Ser342X) variant results in a premature termination codon, predicted to cause a truncated or absent MUT protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.1399C>T, p.Arg467X). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 1/121004 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant was found in methylmalonic acidemia patients in compound heterozigosity with other pathogenic variants such as MUT c.2080C>T, p.Arg694Trp and c.572C>A, p.Ala191Glu (Acquaviva_HumMut_2005, Nizon_Orph J Rare Dis_2013). Taken together, this variant is classified as pathogenic.
Invitae	RCV000665393	SCV000940062	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser342*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs770466993, ExAC 0.002%). This variant has been observed in several individuals affected with MUT-related conditions (PMID: 15643616, 19375370). ClinVar contains an entry for this variant (Variation ID: 495777). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.

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