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NM_000414.4(HSD17B4):c.46G>A (p.Gly16Ser) AND HSD17B4-related disorder

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Oct 16, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000779455.10

Allele description [Variation Report for NM_000414.4(HSD17B4):c.46G>A (p.Gly16Ser)]

NM_000414.4(HSD17B4):c.46G>A (p.Gly16Ser)

Genes:
LOC129994460:ATAC-STARR-seq lymphoblastoid active region 22989 [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.46G>A (p.Gly16Ser)
HGVS:
  • NC_000005.10:g.119452621G>A
  • NG_008182.1:g.5169G>A
  • NM_000414.4:c.46G>AMANE SELECT
  • NM_001199291.3:c.-133G>A
  • NM_001199292.2:c.46G>A
  • NM_001292027.2:c.-92G>A
  • NM_001292028.2:c.-554G>A
  • NP_000405.1:p.Gly16Ser
  • NP_001186221.1:p.Gly16Ser
  • NC_000005.9:g.118788316G>A
  • NM_000414.3:c.46G>A
  • P51659:p.Gly16Ser
Protein change:
G16S; GLY16SER
Links:
UniProtKB: P51659#VAR_037576; OMIM: 601860.0003; dbSNP: rs137853096
NCBI 1000 Genomes Browser:
rs137853096
Molecular consequence:
  • NM_001199291.3:c.-133G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001292027.2:c.-92G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001292028.2:c.-554G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000414.4:c.46G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199292.2:c.46G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
HSD17B4-related disorder
Synonyms:
HSD17B4-Related Disorders; HSD17B4-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000916080Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Pathogenic
(Oct 16, 2018) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004736381PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jun 11, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot 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

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]
PMID:
25967389
See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916080.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The HSD17B4 c.46G>A (p.Gly16Ser) missense variant has been reported in at least five studies and has been identified in at least 29 probands with peroxisomal bifunctional enzyme deficiency, including in 26 individuals in a homozygous state and in three individuals in a compound heterozygous state (van Grunsven et al. 1998; van Grunsven et al. 1999; Ferdinandusse et al. 2006; Konkoľová et al. 2015). The variant was also identified in a compound heterozygous state with a missense variant in one individual with Perrault syndrome (Demain et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000391 in the European (non-Finnish) population of the Genome Aggregation Database. The p.Gly16Ser variant is located at a conserved residue in a loop affecting the binding site of the dehydrogenase region of the protein. Functional studies in yeast expressing the variant and wild type protein showed loss of 3-hydroxyacyl-CoA dehydrogenase activity, but did not affect the enoyl-CoA hydratase activity (van Grunsven et al. 1998). Based on the collective evidence, the p.Gly16Ser variant is classified as pathogenic for HSD17B4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From PreventionGenetics, part of Exact Sciences, SCV004736381.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The HSD17B4 c.46G>A variant is predicted to result in the amino acid substitution p.Gly16Ser. This variant is known to be causative for D-bifunctional protein deficiency and Perrault syndrome, with functional experiments showing this results in inactive dehydrogenase enzymatic activity (van Grunsven et al. 1998. PubMed ID: 9482850; Demain et al. 2016. PubMed ID: 26970254; Pronicka et al. 2016. PubMed ID: 27290639). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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

Last Updated: Nov 10, 2024