Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001261547 | SCV004526687 | likely pathogenic | Mitochondrial trifunctional protein deficiency | 2023-11-20 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 333 of the HADHB protein (p.Pro333Leu). This variant is present in population databases (rs770736746, gnomAD 0.006%). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 35433169). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 916538). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HADHB protein function with a positive predictive value of 80%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004782660 | SCV005394465 | uncertain significance | not specified | 2024-09-13 | criteria provided, single submitter | clinical testing | Variant summary: HADHB c.998C>T (p.Pro333Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.998C>T has been reported in the literature in at least one compound heterozygous individual affected with Mitochondrial Trifunctional Protein Deficiency (Orstavik_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35433169). ClinVar contains an entry for this variant (Variation ID: 916538). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Department of Medical Genetics, |
RCV001261547 | SCV001244852 | uncertain significance | Mitochondrial trifunctional protein deficiency | 2018-08-15 | no assertion criteria provided | clinical testing |