ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.394C>T (p.Arg132Trp)

gnomAD frequency: 0.00002  dbSNP: rs773305477
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670514 SCV000795373 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2017-11-14 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000733584 SCV000861663 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing
Invitae RCV001861793 SCV002228929 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 132 of the HSD17B4 protein (p.Arg132Trp). This variant is present in population databases (rs773305477, gnomAD 0.01%). This missense change has been observed in individual(s) with D-bifunctional protein deficiency and/or Perrault syndrome (PMID: 16385454, 28017249, 34660840). 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: 554818). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670514 SCV002548010 pathogenic Bifunctional peroxisomal enzyme deficiency 2022-05-13 criteria provided, single submitter clinical testing Variant summary: HSD17B4 c.394C>T (p.Arg132Trp) results in a non-conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase domain (Matsukawa_2017) and dimerization of two nucleotide-binding domains (Ferdinandusse_2005) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251292 control chromosomes (gnomAD). c.394C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2005, Yubero+2016, Matsukawa_2016, Alshenaifi_2018, Yamamoto_2021) and this variant co-segregated with the disease (Matsukawa_2016, Yamamoto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000670514 SCV004192372 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2023-10-11 criteria provided, single submitter clinical testing

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