ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.1547T>C (p.Ile516Thr)

gnomAD frequency: 0.00001  dbSNP: rs587777443
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
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, Mass General Brigham Personalized 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, Revvity 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, Inc. RCV000672665 SCV001458669 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.