VCV000495866.20 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

7 out of 9 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 495866 Accession: VCV000495866.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q23.1 5: 119525228 (GRCh38) [ NCBI UCSC ] 5: 118860923 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 17, 2018	Jun 29, 2025	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000414.4:c.1516C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000405.1:p.Arg506Cys	missense
NM_001199291.3:c.1591C>T	NP_001186220.1:p.Arg531Cys	missense
NM_001199292.2:c.1462C>T	NP_001186221.1:p.Arg488Cys	missense
NM_001292027.2:c.1444C>T	NP_001278956.1:p.Arg482Cys	missense
NM_001292028.2:c.1096C>T	NP_001278957.1:p.Arg366Cys	missense
NC_000005.10:g.119525228C>T
NC_000005.9:g.118860923C>T
NG_008182.1:g.77776C>T

... more HGVS ... less HGVS

Protein change

R506C, R366C, R488C, R531C, R482C

Other names

Canonical SPDI

NC_000005.10:119525227:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA3382299 dbSNP: rs766199971 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HSD17B4		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1441	1499

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bifunctional peroxisomal enzyme deficiency	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 21, 2023	RCV000590157.6
Bifunctional peroxisomal enzyme deficiency Perrault syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763126.2
Bifunctional peroxisomal enzyme deficiency Perrault syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 20, 2024	RCV001220352.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 19, 2021	RCV002530904.2
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 24, 2022	RCV002260650.2
Perrault syndrome 1	Pathogenic (1)	criteria provided, single submitter	Mar 17, 2024	RCV003987613.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 16, 2017) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Bifunctional peroxisomal enzyme deficiency	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696690.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 16385454‚ 25967389 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Perrault syndrome 1 Bifunctional peroxisomal enzyme deficiency	Fulgent Genetics, Fulgent Genetics Accession: SCV000893678.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jun 24, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV002540424.2 First in ClinVar: Jul 08, 2022 Last updated: Mar 04, 2023	Comment: show 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) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Perrault syndrome 1	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004805007.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Pathogenic (Feb 19, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Inborn genetic diseases	Ambry Genetics Accession: SCV003723182.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 16385454‚ 22864515‚ 25967389‚ 28649525 Comment: show 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; Konkoová, 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bifunctional peroxisomal enzyme deficiency	Baylor Genetics Accession: SCV004192379.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Perrault syndrome Bifunctional peroxisomal enzyme deficiency Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001392335.6 First in ClinVar: Jul 16, 2020 Last updated: Mar 04, 2025	Publications: PubMed (3) PubMed: 16385454‚ 25967389‚ 22864515 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Bifunctional peroxisomal enzyme deficiency	Natera, Inc. Accession: SCV001458667.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 08, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Bifunctional peroxisomal enzyme deficiency	Counsyl Accession: SCV001132227.2 First in ClinVar: Dec 23, 2019 Last updated: Jun 29, 2025	Publications: PubMed (3) PubMed: 16385454‚ 22864515‚ 25967389 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

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.

Comment:

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)

Comment:

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; Konkoová, 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.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia.	Konkoľová J	Gene	2015	PMID: 25967389
Effects of naturally occurring missense mutations and G525V in the hydratase domain of human d-bifunctional protein on hydratase activity.	Tsuchida S	Molecular genetics and metabolism reports	2014	PMID: 28649525
Hydratase activities of green fluorescent protein tagged human multifunctional enzyme type 2 hydratase domain and its variants.	Tsuchida S	Journal of oleo science	2012	PMID: 22864515
Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis.	Ferdinandusse S	American journal of human genetics	2006	PMID: 16385454

Text-mined citations for rs766199971 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 29, 2025

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs766199971 ...