Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000672665 | SCV000797792 | likely pathogenic | Bifunctional peroxisomal enzyme deficiency | 2018-02-16 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000825530 | SCV000966845 | likely pathogenic | Rare genetic deafness | 2018-04-18 | criteria provided, single submitter | clinical testing | The p.Ile541Thr variant (also referred to as Ile516Thr) in HSD17B4 has been repo rted in 3 individuals with D-bifunctional protein deficiency and segregated with the disease in 1 affected (Ferdinandusse 2006. McMillan 2012). It was absent fr om large population studies. All reported individuals were compound heterozygote s with different missense alleles, including likely pathogenic variants. The p.I le541Thr variant has been reported in ClinVar (Variation ID: 137617). In vitro f unctional data suggest that this mutation impacts protein dimerization, resultin g in reduced function (Ferdinandusse 2006, Tsuchida 2016); however, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis suggest that the p.Ile541Thr variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully es tablish its clinical significance, the p.Ile541Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PM3; PP3; PS3_Supporting |
Invitae | RCV001849905 | SCV002309871 | likely pathogenic | Bifunctional peroxisomal enzyme deficiency; Perrault syndrome | 2023-04-30 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSD17B4 protein function. ClinVar contains an entry for this variant (Variation ID: 137617). This missense change has been observed in individuals with clinical features of HSD17B4-related disorders (PMID: 16385454, 23181892, 24108619, 28708278). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 516 of the HSD17B4 protein (p.Ile516Thr). |
Revvity Omics, |
RCV003144135 | SCV003834661 | likely pathogenic | not provided | 2021-11-15 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000672665 | SCV004192383 | pathogenic | Bifunctional peroxisomal enzyme deficiency | 2023-09-06 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000125466 | SCV000168918 | pathogenic | Perrault syndrome 1 | 2012-11-22 | no assertion criteria provided | literature only | |
Natera, |
RCV000672665 | SCV001458669 | likely pathogenic | Bifunctional peroxisomal enzyme deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |