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NM_000414.4(HSD17B4):c.743G>A (p.Arg248His) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 15, 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.743G>A (p.Arg248His)]

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

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.743G>A (p.Arg248His)
  • 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:
dbSNP: rs748057401
NCBI 1000 Genomes Browser:
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]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV002572320Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Dec 15, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

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



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]

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572320.2

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


Variant summary: HSD17B4 c.743G>A (p.Arg248His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250756 control chromosomes. c.743G>A has been reported in the literature in at least one individual affected with a multisystem progressive disorder, where it was found in compound heterozygosity with a truncating variant (c.590_597dupGATCACGG; p.Met200fs) (Schon_2021). These data alone do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another missense variant affecting the same amino acid (p.Arg248Cys) has been classified as pathogenic by our laboratory in relation to D-Bifunctional Protein Deficiency. The following publication has been ascertained in the context of this evaluation (PMID: 34732400). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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

Last Updated: Jul 7, 2024