ClinVar Genomic variation as it relates to human health
NM_000197.2(HSD17B3):c.239G>A (p.Arg80Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000197.2(HSD17B3):c.239G>A (p.Arg80Gln)
Variation ID: 4874 Accession: VCV000004874.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.32 9: 96254906 (GRCh38) [ NCBI UCSC ] 9: 99017188 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jul 23, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000197.2:c.239G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000188.1:p.Arg80Gln missense NC_000009.12:g.96254906C>T NC_000009.11:g.99017188C>T NG_008157.1:g.52247G>A LRG_1296:g.52247G>A LRG_1296t1:c.239G>A LRG_1296p1:p.Arg80Gln P37058:p.Arg80Gln - Protein change
- R80Q
- Other names
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- Canonical SPDI
- NC_000009.12:96254905:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00015
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HSD17B3 | - | - |
GRCh38 GRCh37 |
9 | 346 | |
SLC35D2-HSD17B3 | - | - | - | GRCh38 | - | 336 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000005150.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2022 | RCV000255553.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 13, 2007 | RCV000581347.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Testosterone 17-beta-dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809687.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002242089.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine with glutamine at codon 80 of the HSD17B3 protein (p.Arg80Gln). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with glutamine at codon 80 of the HSD17B3 protein (p.Arg80Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs119481075, ExAC 0.009%). This missense change has been observed in individuals with pseudohermaphroditism (PMID: 8075637, 8626842, 17551466). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4874). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8075637, 12429500). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322436.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a significant reduction in enzyme activity (Geissler et al., 1994); In silico analysis supports that this missense variant has a deleterious … (more)
Published functional studies demonstrate a significant reduction in enzyme activity (Geissler et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25383892, 8075637, 23295294, 22857144, 22445608, 10599740, 27163392, 29566152, 33984517, 8626842, 31589614, 33144682, 33516834, 33586216) (less)
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Pathogenic
(Aug 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Testosterone 17-beta-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002025033.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Testosterone 17-beta-dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086696.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pseudohermaphroditism, male, with gynecomastia (MIM#264300). (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 glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 8 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 short chain dehydrogenase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with differences of sex development, both as homozygotes or compound heterozygotes; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 22445608, 27898418, 36606580). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(May 01, 1996)
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no assertion criteria provided
Method: literature only
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17-@BETA HYDROXYSTEROID DEHYDROGENASE III DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025327.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In DNA from a member of a large and extensively studied kindred with familial male pseudohermaphroditism due to 17-ketoreductase deficiency (264300) living in the Gaza … (more)
In DNA from a member of a large and extensively studied kindred with familial male pseudohermaphroditism due to 17-ketoreductase deficiency (264300) living in the Gaza strip (Kohn et al., 1985; Eckstein et al., 1989), Geissler et al. (1994) identified homozygosity for a G-to-A transition (CGG to CAG) resulting in an arg80-to-gln substitution at the protein level. Expression analysis demonstrated a small amount of residual activity in cells transfected with the R80Q mutant cDNA consistent with the presence of residual testicular 17-beta-HSD activity demonstrated in this family by Eckstein et al. (1989). Rosler et al. (1996) identified homozygosity for the R80Q mutation in 24 individuals from 9 extended Arab families in Israel. Twenty-one homozygotes were male pseudohermaphrodites (46,XY) with testicular 17-beta-HSD3 deficiency, born with either female-looking external genitalia or various degrees of genital ambiguity. If not reassigned in infancy, they were reared as females until puberty, when marked virilization occurred, often leading to the spontaneous adoption of a male gender role. In contrast, the 3 homozygous females (46,XX) were asymptomatic, had normal internal and external genitalia, normal sexual development, and revealed no biochemical evidence of 17-beta-HSD3 deficiency. The molecular pattern was considered compatible with autosomal recessive inheritance that is sex-dependent. (less)
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Pathogenic
(Jul 13, 2007)
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no assertion criteria provided
Method: clinical testing
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Pseudohermaphroditism
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692115.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Changes in the clinical management of 5α-reductase type 2 and 17β-hydroxysteroid dehydrogenase type 3 deficiencies in France. | Bonnet E | Endocrine connections | 2023 | PMID: 36606580 |
Rapid Molecular Genetic Diagnosis with Next-Generation Sequencing in 46,XY Disorders of Sex Development Cases: Efficiency and Cost Assessment. | Özen S | Hormone research in paediatrics | 2017 | PMID: 27898418 |
Duplication of exons 3-10 of the HSD17B3 gene: a novel type of genetic defect underlying 17β-HSD-3 deficiency. | Neocleous V | Gene | 2012 | PMID: 22445608 |
17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. | Rosler A | Pediatric endocrinology reviews : PER | 2006 | PMID: 17551466 |
Amino acid substitution of arginine 80 in 17beta-hydroxysteroid dehydrogenase type 3 and its effect on NADPH cofactor binding and oxidation/reduction kinetics. | McKeever BM | Biochimica et biophysica acta | 2002 | PMID: 12429500 |
A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females. | Rösler A | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8626842 |
Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. | Geissler WM | Nature genetics | 1994 | PMID: 8075637 |
The nature of the defect in familial male pseudohermaphroditism in Arabs of Gaza. | Eckstein B | The Journal of clinical endocrinology and metabolism | 1989 | PMID: 2918056 |
Kohn, G., Lasch, E. E., El-Shawwa, R., Elrayyes, E., Litvin, Y., Rosler, A. Male pseudohermaphroditism due to 17-beta-hydroxysteroid dehydrogenase deficiency (17-beta-HSD) in a large Arab kinship: studies on the natural history of the defect. J. Pediat. Endocr. 1: 29-37, 1985. | - | - | - | - |
Text-mined citations for rs119481075 ...
HelpRecord last updated Aug 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.