Submissions for variant NM_000414.4(HSD17B4):c.1516C>T (p.Arg506Cys)

gnomAD frequency: 0.00001  dbSNP: rs766199971

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590157	SCV000696690	pathogenic	Bifunctional peroxisomal enzyme deficiency	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The HSD17B4 c.1516C>T (p.Arg506Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120420 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic HSD17B4 variant (0.002958). The variant has been reported in affected individuals in the literature both in the homozygous and compound heterozygous state. Additionally, functional studies have shown the variant to abolish hydratase activity (Tsuchida_2015). Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763126	SCV000893678	likely pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001220352	SCV001392335	pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2023-11-13	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 506 of the HSD17B4 protein (p.Arg506Cys). This variant is present in population databases (rs766199971, gnomAD 0.003%). This missense change has been observed in individuals with HSD17B4-related conditions (PMID: 16385454, 25967389). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495866). 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. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002260650	SCV002540424	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (abolition of hydratase activity) (Tsuchida et al., 2012); Not observed at a 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: 28649525, 22864515, 31589614, 16385454, 25967389)
Ambry Genetics	RCV002530904	SCV003723182	pathogenic	Inborn genetic diseases	2021-02-19	criteria provided, single submitter	clinical testing	The c.1516C>T (p.R506C) alteration is located in exon 18 (coding exon 18) of the HSD17B4 gene. This alteration results from a C to T substitution at nucleotide position 1516, causing the arginine (R) at amino acid position 506 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD) database, the HSD17B4 c.1516C>T alteration was observed in <0.01% (4/282248) of total alleles studied. This mutation has been identified in three homozygous and one compound heterozygous individual with D-bifunctional protein deficiency (Ferdinandusse, 2006; Konkoov&aacute;, 2015). Functional studies in E. coli demonstrated that this variant abolished hydratase activity (Tsuchida, 2012; Tsuchida, 2015). The p.R506C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000590157	SCV004192379	pathogenic	Bifunctional peroxisomal enzyme deficiency	2023-09-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987613	SCV004805007	pathogenic	Perrault syndrome 1	2024-03-17	criteria provided, single submitter	research
Counsyl	RCV000590157	SCV001132227	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2018-10-08	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000590157	SCV001458667	pathogenic	Bifunctional peroxisomal enzyme deficiency	2020-09-16	no assertion criteria provided	clinical testing