Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001234309 | SCV001406947 | pathogenic | Methylmalonic aciduria and homocystinuria type cblD | 2023-02-13 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 960731). This sequence change creates a premature translational stop signal (p.Arg216*) in the MMADHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMADHC are known to be pathogenic (PMID: 18385497). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MMADHC-related conditions. 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, |
RCV003226449 | SCV003923096 | pathogenic | Cobalamin C disease | 2023-03-02 | criteria provided, single submitter | clinical testing | Variant summary: MMADHC c.646C>T (p.Arg216X) 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 associated with Methylmalonic Acidemia With Homocystinuria in HGMD. The variant allele was found at a frequency of 4e-06 in 250912 control chromosomes. To our knowledge, no occurrence of c.646C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria has been reported. At least one publication reports experimental evidence showing that this variant results in a truncated protein (Torices_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Gene |
RCV003238852 | SCV003936519 | likely pathogenic | not provided | 2022-12-23 | criteria provided, single submitter | clinical testing | Published functional studies suggest the variant may lead to expression of truncated protein (Torices et al., 2021); however, additional data is needed; Nonsense variant predicted to result in protein truncation, as the last 81 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33552904) |