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NM_000414.4(HSD17B4):c.743G>A (p.Arg248His) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 17, 2023
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:
RCV001856978.3

Allele description [Variation Report for NM_000414.4(HSD17B4):c.743G>A (p.Arg248His)]

NM_000414.4(HSD17B4):c.743G>A (p.Arg248His)

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.743G>A (p.Arg248His)
HGVS:
  • NC_000005.10:g.119493821G>A
  • NG_008182.1:g.46369G>A
  • NM_000414.4:c.743G>AMANE SELECT
  • NM_001199291.3:c.818G>A
  • NM_001199292.2:c.689G>A
  • NM_001292027.2:c.671G>A
  • NM_001292028.2:c.323G>A
  • NP_000405.1:p.Arg248His
  • NP_001186220.1:p.Arg273His
  • NP_001186221.1:p.Arg230His
  • NP_001278956.1:p.Arg224His
  • NP_001278957.1:p.Arg108His
  • NC_000005.9:g.118829516G>A
  • NM_000414.3:c.743G>A
Protein change:
R108H
Links:
dbSNP: rs748057401
NCBI 1000 Genomes Browser:
rs748057401
Molecular consequence:
  • NM_000414.4:c.743G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199291.3:c.818G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199292.2:c.689G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001292027.2:c.671G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001292028.2:c.323G>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
Name:
Perrault syndrome
Synonyms:
Gonadal dysgenesis with auditory dysfunction, autosomal recessive inheritance
Identifiers:
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)
OriginMethodCitations
SCV002258841Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Dec 17, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, IbaƱez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, et al.

BMJ. 2021 Nov 3;375:e066288. doi: 10.1136/bmj-2021-066288.

PubMed [citation]
PMID:
34732400
PMCID:
PMC8565085

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
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002258841.3

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 248 of the HSD17B4 protein (p.Arg248His). This variant is present in population databases (rs748057401, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of HSD17B4-related conditions (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 430263). 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. This variant disrupts the p.Arg248 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16385454, 23308274, 27528516). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Jul 7, 2024