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NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His) AND Bifunctional peroxisomal enzyme deficiency

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Aug 24, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000670512.5

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

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

Gene:
HSD17B4:hydroxysteroid 17-beta dehydrogenase 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q23.1
Genomic location:
Preferred name:
NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)
HGVS:
  • 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:
R366H
Links:
dbSNP: rs1554068136
NCBI 1000 Genomes Browser:
rs1554068136
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]

Condition(s)

Name:
Bifunctional peroxisomal enzyme deficiency (DBIF)
Synonyms:
D-bifunctional protein deficiency; DBP deficiency; D-bifunctional enzyme deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009855; MedGen: C0342870; OMIM: 261515

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000795371Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(Nov 13, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002600631Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Oct 21, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV003921895Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 23, 2022)
paternalclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004192389Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 24, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis.

Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T.

Am J Hum Genet. 2006 Jan;78(1):112-24. Epub 2005 Nov 15.

PubMed [citation]
PMID:
16385454
PMCID:
PMC1380208

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]
PMID:
22864515
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000795371.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600631.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: HSD17B4 c.1517G>A (p.Arg506His) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.1517G>A (p.R506H) has been reported in the literature in at least one homozygous individual affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2006). In addition, another variant (R506C) at the same residue was found in three homozygous patients affected with DBP II (Ferdinandusse_2006) and this variant has been classified as DV in our lab, suggesting this residue is clinical and fuctional important. These data indicate that the variant may be associated with disease. At least one publication reports the hydratase activity was abolished by this variant (Tsuchida_2012). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921895.1

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

Description

0102 - Loss of function is a known mechanism of disease in this gene and is associated with D-bifunctional protein deficiency (MIM#261515) and Perrault syndrome 1 (MIM#233400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MaoC-like domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg506Cys) variant has been reported in three individuals with DBP deficiency (PMID: 16385454), and as likely pathogenic/pathogenic in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as homozygous in an individual with D-bifunctional protein deficiency (PMID: 16385454). The variant has also been reported as a VUS in ClinVar however no further evidence was provided. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1006 - Clinically accredited laboratory assay shows abnormal function of product not specific to the gene. VLCFA assay showed abnormal result in this individual (personal communication). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000414.3:c.31dupG, p.(Val11Glyfs*30)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004192389.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 5, 2024