ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.742C>T (p.Arg248Cys)

gnomAD frequency: 0.00001  dbSNP: rs969485098
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409273 SCV000486928 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2016-09-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409273 SCV000917534 pathogenic Bifunctional peroxisomal enzyme deficiency 2018-09-28 criteria provided, single submitter clinical testing Variant summary: HSD17B4 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function (MutationTaster not captured here due to low p-value). The variant allele was found at a frequency of 8.1e-06 in 245518 control chromosomes (gnomAD). c.742C>T has been reported in the literature in multiple individuals affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Mehtala_2013). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000815715 SCV000956181 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2023-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 248 of the HSD17B4 protein (p.Arg248Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with D-bifunctional protein (DBP) deficiency or Perrault syndrome (PMID: 16385454, 27528516). This variant is also known as p.Arg273Cys. ClinVar contains an entry for this variant (Variation ID: 371366). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 23308274). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001840499 SCV002099593 pathogenic not provided 2022-02-28 criteria provided, single submitter clinical testing Published functional studies demonstrated reduced enzyme kinetic performance compared to wild type by enzyme assay, with partial enzyme activity retained (Mehtala et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23308274, 27528516, 29482223, 32528852, 31589614, 34426522, 16385454)
Baylor Genetics RCV000409273 SCV004192371 pathogenic Bifunctional peroxisomal enzyme deficiency 2023-10-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000409273 SCV002075406 pathogenic Bifunctional peroxisomal enzyme deficiency 2021-04-09 no assertion criteria provided clinical testing

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