ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.1369A>T (p.Asn457Tyr) (rs137853097)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008095 SCV000485179 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2015-12-17 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477799 SCV000536760 likely pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1 2015-12-15 no assertion criteria provided research
GeneDx RCV000385297 SCV000329591 pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The N457Y pathogenic variant in the HSD17B4 gene has been reported multiple times previously in both the homozygous state and compound heterozygous state in patients with D-bifunctional protein deficiency (van Grunsven et al., 1999; Nascimento et al., 2015; Ferdinandusse et al., 2006). The N457Y variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The N457Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The N457Y variant is located in the enoyl-CoA hydratese domain, and it has been shown to disrupt domain folding and reduce hydratase activity to less than 10% of wild type (Tsuchida et al., 2012). We interpret N457Y as a pathogenic variant.
Invitae RCV000684773 SCV000632655 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 457 of the HSD17B4 protein (p.Asn457Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs137853097, ExAC 0.003%). This variant has been reported as homozygous or in combination with another HSD17B4 variant in many individuals affected with D-bifunctional protein deficiency and is considered to be one of the most common pathogenic variants in this gene (PMID: 16385454, 23181892, 25882080, 10400999). Experimental studies have shown that this missense change reduces HSD17B4 hydratase activity to 10-60% of wild-type levels (PMID: 22864515, 10400999). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008095 SCV000028300 pathogenic Bifunctional peroxisomal enzyme deficiency 1999-08-01 no assertion criteria provided literature only

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