Submissions for variant NM_000255.4(MMUT):c.671_678dup (p.Val227fs)

dbSNP: rs758008398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670315	SCV000795151	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-10-27	criteria provided, single submitter	clinical testing
Invitae	RCV001376616	SCV000830987	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val227Asnfs*16) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs758008398, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria (PMID: 15781192, 23045948). ClinVar contains an entry for this variant (Variation ID: 554641). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293582	SCV001482194	pathogenic	Methylmalonic acidemia	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: MUT c.671_678dupAATTTATG (p.Val227AsnfsX16) 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. The variant allele was found at a frequency of 2.8e-05 in 250384 control chromosomes (gnomAD). c.671_678dupAATTTATG has been reported in the literature, in the homozygous and compound heterozygous states, in multiple individuals affected with Methylmalonic Acidemia (e.g. Martinez_2005, Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000670315	SCV004046016	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 3 of13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with methylmalonic aciduria (PMID: 15781192, 23045948). Loss-of-function variation in MUT is an established mechanism of disease (PMID: 15781192). The c.671_678dup (p.Val227AsnfsTer16) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (7/250384), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.671_678dup (p.Val227AsnfsTer16) variant is classified as Pathogenic.
Natera, Inc.	RCV001271715	SCV001453063	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing