Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001047008 | SCV001210937 | likely pathogenic | Mitochondrial trifunctional protein deficiency | 2019-05-06 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with HADHB-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HADHB are known to be pathogenic (PMID: 9259266, 12754706). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 5 of the HADHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001047008 | SCV002819523 | likely pathogenic | Mitochondrial trifunctional protein deficiency | 2022-12-14 | criteria provided, single submitter | clinical testing | Variant summary: HADHB c.255-2A>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 a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251374 control chromosomes (gnomAD v2.1, exomes dataset). To our knowledge, no occurrence of c.255-2A>G in individuals affected with Mitochondrial Trifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |