ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.331C>T (p.Arg111Ter) (rs121918242)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001489 SCV000485884 pathogenic Methylmalonic acidemia with homocystinuria 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000186026 SCV000238988 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The R111X nonsense variant is a common variant that was identified on 36 of 204 alleles (17.6%) of patients with methylmalonic aciduria and homocystinuria, cobalamin C type and is associated with early-onset disease when homozygous (Lerner-Ellis et al., 2006). The R111X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R111X as a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000001489 SCV000845400 pathogenic Methylmalonic acidemia with homocystinuria 2018-08-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000001489 SCV000699397 pathogenic Methylmalonic acidemia with homocystinuria 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.331C>T (p.Arg111X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in vitro study showed mRNA leves in cell lines that are homozygotes for c.331C>T showed ~60% decrease compared to wild-type cell lines (Lerner-Ellis_2009), suggesting this nonsense variant leads to nonsense mediated mRNA decay. One in silico tool predicts a damaging outcome for this variant. This variant was found in 9/120818 control chromosomes at a frequency of 0.0000745, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). This variant has been shown to be one of the most common pathogenic variant in CBLC patients and tend to lead to early onset type of disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.
Invitae RCV000001489 SCV000762782 pathogenic Methylmalonic acidemia with homocystinuria 2018-07-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg111*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121918242, ExAC 0.01%). This variant has been reported in many individuals affected with affected with methylmalonic aciduria and homocystinuria, cblC type (PMID: 16311595, 16714133, 18164228, 24126030). ClinVar contains an entry for this variant (Variation ID: 1424). Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000001489 SCV000711789 pathogenic Methylmalonic acidemia with homocystinuria 2016-03-28 criteria provided, single submitter clinical testing The p.Arg111X variant in MMACHC has been reported in at least 29 individuals (9 homozygotes and 20 compound heterozygotes) with methymalonic aciduria and homocy stinuria, cbIC type (Lerner-Ellis 2006). It has been associated with early onset disease (Lerner-Ellis 2006). This variant has been identified in 9/120714 chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs121918242). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. This nonsense variant leads to a premature termination codon at position 1 11, which is predicted to lead to a truncated or absent protein. Loss of functio n of the MMACHC gene is an established disease mechanism for methymalonic acidur ia. In summary, this variant meets our criteria to be classified as pathogenic f or methymalonic aciduria and homocystinuria, cbIC type based upon its co-occurre nce with disease-causing variants in affected individuals, low frequency in cont rol populations, and predicted functional impact.
OMIM RCV000001489 SCV000021644 pathogenic Methylmalonic acidemia with homocystinuria 2009-07-01 no assertion criteria provided literature only

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