Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
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, |
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, |
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, |
RCV000023785 | SCV001622425 | pathogenic | Cobalamin C disease | 2021-05-13 | criteria provided, single submitter | clinical testing | |
Beijing Key Laboratry for Genetics of Birth Defects, |
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- |
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, |
RCV000023785 | SCV000899210 | pathogenic | Cobalamin C disease | no assertion criteria provided | case-control | ||
Neurology Department, |
RCV000023785 | SCV001423143 | pathogenic | Cobalamin C disease | 2020-04-23 | no assertion criteria provided | research | |
Natera, |
RCV001275215 | SCV001460139 | pathogenic | Methylmalonic acidemia with homocystinuria cblC | 2020-09-16 | no assertion criteria provided | clinical testing | |
Gene |
RCV002513204 | SCV003354480 | not provided | Disorders of Intracellular Cobalamin Metabolism | no assertion provided | literature only | Common in people of Chinese ancestry. | |
Developmental and Behavioral Pediatrics, |
RCV000023785 | SCV003838960 | pathogenic | Cobalamin C disease | no assertion criteria provided | clinical testing |