ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2020-10-14 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002204 SCV001160078 pathogenic not specified 2018-11-28 criteria provided, single submitter clinical testing The HSD17B4 c.1444A>T; p.Asn482Tyr variant (rs137853097), also known as p.Asn457Tyr, is reported in the literature in individuals affected with D-bifunctional protein deficiency, both in the homozygous state and in trans to a pathogenic variant (Ferdinandusse 2006, Nascimento 2015, van Grunsven 1999). Biochemical assays of hydratase function indicate that the p.Asn482Tyr variant has severely impaired enzymatic activity (Tsuchida 2012, van Grunsven 1999). Additionally, another variant at this codon (p.Asn482Asp) has been reported in an individual with D-bifunctional protein deficiency (Ferdinandusse 2006) and was demonstrated to have negligible hydratase activity (Tsuchida 2012). The p.Asn482Tyr variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 7656) and it is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 482 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Ferdinandusse S et al. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am J Hum Genet. 2006 Jan;78(1):112-24. Nascimento J et al. D-bifunctional protein deficiency: a cause of neonatal onset seizures and hypotonia. Pediatr Neurol. 2015 May;52(5):539-43. Tsuchida S et al. Hydratase activities of green fluorescent protein tagged human multifunctional enzyme type 2 hydratase domain and its variants. J Oleo Sci. 2012;61(8):443-50. van Grunsven EG et al. Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency. Hum Mol Genet. 1999 Aug;8(8):1509-16.
Myriad Women's Health, Inc. RCV000008095 SCV001194040 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2019-12-09 criteria provided, single submitter clinical testing NM_000414.3(HSD17B4):c.1369A>T(N457Y) is classified as likely pathogenic in the context of D-bifunctional protein deficiency. Sources cited for classification include the following: PMID 12562856, 16385454 and 10400999. Classification of NM_000414.3(HSD17B4):c.1369A>T(N457Y) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008095 SCV001362501 pathogenic Bifunctional peroxisomal enzyme deficiency 2019-10-17 criteria provided, single submitter clinical testing Variant summary: HSD17B4 c.1369A>T (p.Asn457Tyr) results in a non-conservative amino acid change in 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 1.6e-05 in 251434 control chromosomes. c.1369A>T has been reported in the literature in multiple individuals affected with D-Bifunctional Protein Deficiency (vanGrunsven_1999, Nascimento_2015). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (vanGrunsven_1999, Tsuchida_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000008095 SCV000028300 pathogenic Bifunctional peroxisomal enzyme deficiency 1999-08-01 no assertion criteria provided literature only
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

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