ClinVar Genomic variation as it relates to human health
NM_000197.2(HSD17B3):c.645A>T (p.Glu215Asp)
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.645A>T (p.Glu215Asp)
Variation ID: 2440772 Accession: VCV002440772.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.32 9: 96244356 (GRCh38) [ NCBI UCSC ] 9: 99006638 (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 Mar 5, 2023 Sep 29, 2024 May 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000197.2:c.645A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000188.1:p.Glu215Asp missense NM_000197.1:c.645A>T NR_182427.1:n.3412A>T NC_000009.12:g.96244356T>A NC_000009.11:g.99006638T>A NG_008157.1:g.62797A>T LRG_1296:g.62797A>T LRG_1296t1:c.645A>T LRG_1296p1:p.Glu215Asp - Protein change
- E215D
- Other names
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- Canonical SPDI
- NC_000009.12:96244355:T:A
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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
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 | 347 | |
SLC35D2-HSD17B3 | - | - | - | GRCh38 | - | 337 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 23, 2024 | RCV003146073.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV003561189.2 |
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
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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
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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
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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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Likely pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Testosterone 17-beta-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV004190285.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
ACMG:PM2 PP3 PP4
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Likely pathogenic
(Dec 14, 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:
germline
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Revvity Omics, Revvity
Accession: SCV003829108.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004277996.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 215 of the HSD17B3 … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 215 of the HSD17B3 protein (p.Glu215Asp). This variant is present in population databases (rs115063639, gnomAD 0.009%). This missense change has been observed in individual(s) with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 10599740, 17466011, 27163392, 27899157, 30668521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2440772). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 23, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005184994.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: HSD17B3 c.645A>T (p.Glu215Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: HSD17B3 c.645A>T (p.Glu215Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HSD17B3 causing Testosterone 17-beta-dehydrogenase deficiency, allowing no conclusion about variant significance. c.645A>T has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency, including homozygotes (Andersson_1996, Mendonca_1999, Lee_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 17466011, 10022457). ClinVar contains an entry for this variant (Variation ID: 2440772). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 05, 2023)
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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: SCV005326069.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate a damaging effect with a near complete loss of enzyme activity (PMID: 8550739); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate a damaging effect with a near complete loss of enzyme activity (PMID: 8550739); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10599740, 25298885, 8550739, 34946839, 17466011, 27899157, 36077423, 35134971, 35065919, 33984517, 35432193, 36675662, 30668521, 27163392) (less)
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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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Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD). | Hughes LA | Endocrine connections | 2019 | PMID: 30668521 |
46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency. | Mendonca BB | The Journal of steroid biochemistry and molecular biology | 2017 | PMID: 27163392 |
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. | Eggers S | Genome biology | 2016 | PMID: 27899157 |
Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. | Lee YS | Clinical endocrinology | 2007 | PMID: 17466011 |
17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. | Boehmer AL | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10599740 |
17Beta-hydroxysteroid dehydrogenase 3 deficiency in women. | Mendonca BB | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10022457 |
Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. | Andersson S | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8550739 |
Text-mined citations for this variant ...
HelpRecord last updated Oct 08, 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.