ClinVar Miner

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

dbSNP: rs137853097
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000385297 SCV000329591 pathogenic not provided 2023-03-20 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant disrupts domain folding and reduces hydratase activity to less than 10% of wild type (van Grunsven et al., 1999; Tsuchida et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10400999, 22864515, 25882080, 25967389, 16385454, 31589614)
Invitae RCV000684773 SCV000632655 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 457 of the HSD17B4 protein (p.Asn457Tyr). This variant is present in population databases (rs137853097, gnomAD 0.006%). This missense change has been observed in individuals with D-bifunctional protein deficiency (PMID: 10400999, 16385454, 23181892, 25882080). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7656). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 10400999, 22864515). 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 Genetics, 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000008095 SCV002512231 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2021-04-02 criteria provided, single submitter clinical testing ACMG classification criteria: PS4 moderate, PM2, PM3, PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000008095 SCV002526679 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2022-05-06 criteria provided, single submitter clinical testing This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3_SUP, PM2_SUP, PP3
3billion RCV000008095 SCV002572656 pathogenic Bifunctional peroxisomal enzyme deficiency 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007656). A different missense change at the same codon (p.Asn457Asp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000371413). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV000477799 SCV002791043 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1 2021-08-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV000008095 SCV004192381 pathogenic Bifunctional peroxisomal enzyme deficiency 2023-09-14 criteria provided, single submitter clinical testing
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
Natera, Inc. RCV000008095 SCV002075415 pathogenic Bifunctional peroxisomal enzyme deficiency 2020-07-22 no assertion criteria provided clinical testing

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