Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002238620 | SCV002511734 | likely pathogenic | Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome | 2022-04-26 | criteria provided, single submitter | clinical testing | Variant summary: TBCD c.1224-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the normal 3' acceptor site and strengthens/creates an alternate cryptic exonic one. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-06 in 150916 control chromosomes (gnomAD v3.1.2). To our knowledge, no occurrence of c.1224-2A>G in individuals affected with Encephalopathy, Early Onset and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV003093920 | SCV003024539 | pathogenic | not provided | 2022-11-05 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1683318). Disruption of this splice site has been observed in individual(s) with TBCD-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change affects an acceptor splice site in intron 12 of the TBCD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCD are known to be pathogenic (PMID: 27666370, 27666374). |