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NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 12, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)]

NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)

HSD17B4:hydroxysteroid 17-beta dehydrogenase 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)
  • NC_000005.10:g.119525229G>A
  • NG_008182.1:g.77777G>A
  • NM_000414.4:c.1517G>AMANE SELECT
  • NM_001199291.3:c.1592G>A
  • NM_001199292.2:c.1463G>A
  • NM_001292027.2:c.1445G>A
  • NM_001292028.2:c.1097G>A
  • NP_000405.1:p.Arg506His
  • NP_001186220.1:p.Arg531His
  • NP_001186221.1:p.Arg488His
  • NP_001278956.1:p.Arg482His
  • NP_001278957.1:p.Arg366His
  • NC_000005.9:g.118860924G>A
  • NM_000414.3:c.1517G>A
Protein change:
dbSNP: rs1554068136
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000414.4:c.1517G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199291.3:c.1592G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199292.2:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001292027.2:c.1445G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001292028.2:c.1097G>A - missense variant - [Sequence Ontology: SO:0001583]


Bifunctional peroxisomal enzyme deficiency (DBIF)
D-bifunctional protein deficiency; DBP deficiency; D-bifunctional enzyme deficiency; See all synonyms [MedGen]
MONDO: MONDO:0009855; MedGen: C0342870; OMIM: 261515
Perrault syndrome
Gonadal dysgenesis with auditory dysfunction, autosomal recessive inheritance
MONDO: MONDO:0017312; MedGen: C0685838; Orphanet: 2855; OMIM: PS233400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Sep 12, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia.

Konkoľová J, Petrovič R, Chandoga J, Repiský M, Zelinková H, Kršiaková J, Kolníková M, Kantarská D, Šutovský S, Böhmer D.

Gene. 2015 Aug 15;568(1):61-8. doi: 10.1016/j.gene.2015.05.020. Epub 2015 May 9.

PubMed [citation]

Hydratase activities of green fluorescent protein tagged human multifunctional enzyme type 2 hydratase domain and its variants.

Tsuchida S, Kawamoto K, Endo N, Nunome K, Hamaue N, Aoki T.

J Oleo Sci. 2012;61(8):443-50.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004569604.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg506 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16385454, 25967389). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). 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. ClinVar contains an entry for this variant (Variation ID: 554817). This missense change has been observed in individual(s) with D-bifunctional protein deficiency (PMID: 16385454). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 506 of the HSD17B4 protein (p.Arg506His).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 5, 2024