ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter) (rs587776889)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756343 SCV000884123 pathogenic not provided 2017-07-25 criteria provided, single submitter clinical testing The p.Trp203Ter variant creates a termination codon in the MMACHC protein at codon 203 in exon 4 which is predicted to result in a truncated or absent protein product. In a cohort of 204 individuals suspected with inborn errors in cobalamin metabolism, the p.Trp203Ter was identified in the MMACHC gene from 7 individuals with pathogenic bi-allelic variants, including 5 homozygotes (Lerner-Ellis et. al. 2006). Furthermore, the p.Trp203Ter was observed in 52 out of 71 Chinese patients, including 15 homozygotes with elevated methylmalonic aciduria (MMA) and homocystinuria (HC), whereby haplotype analysis determined that it may have been caused by a founder effect in this population (Liu et. al. 2010). This variant is reported in ClinVar (Variation ID: 30800) as pathogenic. It is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 246,224 chromosomes). Based on these observations the p.Trp203Ter is pathogenic.
Biochemistry Laboratory of CDMU,Chengde Medical University RCV000023785 SCV000899210 pathogenic Methylmalonic acidemia with homocystinuria no assertion criteria provided case-control
Counsyl RCV000023785 SCV000790396 pathogenic Methylmalonic acidemia with homocystinuria 2017-03-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000023785 SCV000894028 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000023785 SCV000699402 pathogenic Methylmalonic acidemia with homocystinuria 2017-07-13 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.609G>A (p.Trp203X) 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 silico tool predicts a damaging outcome for this variant. This variant was found in 4/121366 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the homozygous and compound heterozygous state, and there is evidence the variant may be a founder mutation in the Chinese population (Lerner-Ellis_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000023785 SCV000949474 pathogenic Methylmalonic acidemia with homocystinuria 2018-11-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MMACHC gene (p.Trp203*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 80 amino acids of the MMACHC protein This variant is present in population databases (rs587776889, ExAC 0.05%). This variant has been observed in individuals affected with MMACHC-related conditions (PMID: 16311595, 28327205, 27383490, 20631720, 23954310). ClinVar contains an entry for this variant (Variation ID: 30800). A different variant (c.608G>A) giving rise to the same protein effect observed here (p.Trp203*) has been reported in multiple individuals affected with MMACHC-related conditions (PMID: 16311595, 23954310, 25772322). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000023785 SCV000045076 pathogenic Methylmalonic acidemia with homocystinuria 2010-09-01 no assertion criteria provided literature only

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