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NM_000414.4(HSD17B4):c.394C>T (p.Arg132Trp) AND Bifunctional peroxisomal enzyme deficiency

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Feb 4, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000670514.4

Allele description [Variation Report for NM_000414.4(HSD17B4):c.394C>T (p.Arg132Trp)]

NM_000414.4(HSD17B4):c.394C>T (p.Arg132Trp)

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.394C>T (p.Arg132Trp)
HGVS:
  • NC_000005.10:g.119477461C>T
  • NG_008182.1:g.30009C>T
  • NM_000414.4:c.394C>TMANE SELECT
  • NM_001199291.3:c.469C>T
  • NM_001199292.2:c.340C>T
  • NM_001292027.2:c.322C>T
  • NM_001292028.2:c.-18C>T
  • NP_000405.1:p.Arg132Trp
  • NP_001186220.1:p.Arg157Trp
  • NP_001186221.1:p.Arg114Trp
  • NP_001278956.1:p.Arg108Trp
  • NC_000005.9:g.118813156C>T
  • NM_000414.3:c.394C>T
Protein change:
R108W
Links:
dbSNP: rs773305477
NCBI 1000 Genomes Browser:
rs773305477
Molecular consequence:
  • NM_001292028.2:c.-18C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000414.4:c.394C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199291.3:c.469C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199292.2:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001292027.2:c.322C>T - 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
SCV000795373Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Likely pathogenic
(Nov 14, 2017)
unknownclinical testing

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

Citation Link,

SCV002548010Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(May 13, 2022)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004192372Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 4, 2024)
unknownclinical testing

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

Summary from all submissions

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

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism.

Yubero D, Brandi N, Ormazabal A, Garcia-Cazorla À, Pérez-Dueñas B, Campistol J, Ribes A, Palau F, Artuch R, Armstrong J; Working Group..

PLoS One. 2016;11(5):e0156359. doi: 10.1371/journal.pone.0156359.

PubMed [citation]
PMID:
27243974
PMCID:
PMC4887012
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000795373.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002548010.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: HSD17B4 c.394C>T (p.Arg132Trp) results in a non-conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase domain (Matsukawa_2017) and dimerization of two nucleotide-binding domains (Ferdinandusse_2005) of 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 2.8e-05 in 251292 control chromosomes (gnomAD). c.394C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2005, Yubero+2016, Matsukawa_2016, Alshenaifi_2018, Yamamoto_2021) and this variant co-segregated with the disease (Matsukawa_2016, Yamamoto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Baylor Genetics, SCV004192372.2

#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: Jun 17, 2024