ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs587776889
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000023785 SCV000699402 pathogenic Cobalamin C disease 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.
Counsyl RCV000023785 SCV000790396 pathogenic Cobalamin C disease 2017-03-17 criteria provided, single submitter clinical testing
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.
Fulgent Genetics, Fulgent Genetics RCV000023785 SCV000894028 pathogenic Cobalamin C disease 2022-02-02 criteria provided, single submitter clinical testing
Invitae RCV000023785 SCV000949474 pathogenic Cobalamin C disease 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp203*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs587776889, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with MMACHC-related conditions (PMID: 16311595, 20631720, 23954310, 25772322, 27383490, 28327205). ClinVar contains an entry for this variant (Variation ID: 30800). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000023785 SCV001162918 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV000023785 SCV001622425 pathogenic Cobalamin C disease 2021-05-13 criteria provided, single submitter clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital RCV000023785 SCV001739475 pathogenic Cobalamin C disease 2020-02-28 criteria provided, single submitter clinical testing
3billion RCV000023785 SCV002012349 pathogenic Cobalamin C disease 2021-10-02 criteria provided, single submitter clinical testing Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000441, PM2). he variant was observed in trans with a pathogenic variant (NM_015506.2: c.394C>T) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000030800.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab RCV000023785 SCV004178208 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000023785 SCV000045076 pathogenic Cobalamin C disease 2010-09-01 no assertion criteria provided literature only
Biochemistry Laboratory of CDMU, Chengde Medical University RCV000023785 SCV000899210 pathogenic Cobalamin C disease no assertion criteria provided case-control
Neurology Department, Peking University First Hospital RCV000023785 SCV001423143 pathogenic Cobalamin C disease 2020-04-23 no assertion criteria provided research
Natera, Inc. RCV001275215 SCV001460139 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing
GeneReviews RCV002513204 SCV003354480 not provided Disorders of Intracellular Cobalamin Metabolism no assertion provided literature only Common in people of Chinese ancestry.
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University RCV000023785 SCV003838960 pathogenic Cobalamin C disease no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.