ClinVar Genomic variation as it relates to human health
NM_000198.4(HSD3B2):c.776C>T (p.Thr259Met)
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_000198.4(HSD3B2):c.776C>T (p.Thr259Met)
Variation ID: 12192 Accession: VCV000012192.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p12 1: 119422277 (GRCh38) [ NCBI UCSC ] 1: 119964900 (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 8, 2016 Apr 15, 2024 Feb 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000198.4:c.776C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000189.1:p.Thr259Met missense NM_001166120.2:c.776C>T NP_001159592.1:p.Thr259Met missense NC_000001.11:g.119422277C>T NC_000001.10:g.119964900C>T NG_013349.1:g.12347C>T P26439:p.Thr259Met - Protein change
- T259M
- Other names
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- Canonical SPDI
- NC_000001.11:119422276: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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HSD3B2 | - | - |
GRCh38 GRCh37 |
304 | 366 |
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 22, 2022 | RCV000012975.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2023 | RCV001039417.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2024 | RCV002222349.2 |
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
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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3 beta-Hydroxysteroid dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521701.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.03). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HSD3B2 related disorder (ClinVar ID: VCV000012192 / PMID: 10599696). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10599696, 10770215, 10973654). A different missense change at the same codon (p.Thr259Arg) has been reported to be associated with HSD3B2 related disorder (PMID: 7633460). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hyponatremia (present) , Hyperkalemia (present) , Hyperpigmentation of the skin (present) , Labial hypertrophy (present) , Elevated serum 11-deoxycortisol (present) , Increased serum testosterone level … (more)
Hyponatremia (present) , Hyperkalemia (present) , Hyperpigmentation of the skin (present) , Labial hypertrophy (present) , Elevated serum 11-deoxycortisol (present) , Increased serum testosterone level (present) , Adrenocorticotropic hormone excess (present) (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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3 beta-Hydroxysteroid dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806301.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 10, 2023)
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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: SCV001202947.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr259 amino acid residue in HSD3B2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr259 amino acid residue in HSD3B2. Other variant(s) that disrupt this residue have been observed in individuals with HSD3B2-related conditions (PMID: 7633460, 10599696), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HSD3B2 function (PMID: 10599696, 11196452). 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 HSD3B2 protein function. ClinVar contains an entry for this variant (Variation ID: 12192). This missense change has been observed in individuals with clinical features of congenital adrenal hyperplasia (PMID: 10599696, 10770215, 10973654). This variant is present in population databases (rs80358221, gnomAD 0.008%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 259 of the HSD3B2 protein (p.Thr259Met). (less)
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Pathogenic
(Feb 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal hyperplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500775.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 15, 2024 |
Comment:
Variant summary: HSD3B2 c.776C>T (p.Thr259Met) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR002225) of the encoded protein sequence. … (more)
Variant summary: HSD3B2 c.776C>T (p.Thr259Met) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR002225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251122 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.776C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Adrenal Hyperplasia (e.g., Lutfallah_2002, Marui_2000, Moisan_1999, Zhang_1999). 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, finding that the variant resulted in <10% of normal enzymatic activity in COS-1 cells (e.g., Zhang_1999). The following publications have been ascertained in the context of this evaluation (PMID: 12050224, 10973654, 10599696, 10770215). ClinVar contains an entry for this variant (Variation ID: 12192). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 01, 2000)
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no assertion criteria provided
Method: literature only
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ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 3-BETA-HYDROXYSTEROID DEHYDROGENASE 2 DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033220.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2016 |
Comment on evidence:
In 2 French sibs with salt-wasting CAH due to 3-beta-HSD deficiency (201810), Moisan et al. (1999) found a heterozygous C-to-T transition in exon 4 of … (more)
In 2 French sibs with salt-wasting CAH due to 3-beta-HSD deficiency (201810), Moisan et al. (1999) found a heterozygous C-to-T transition in exon 4 of the HSD3B2 gene that converted codon 259 from thr to met (T259M). A frameshift mutation was found on the other allele (613890.0010). The elder sib was a male with perineal hypospadias with palpable testes in a bifid scrotum. The younger sib, a female, had normal external genitalia at birth. Zhang et al. (2000) found this mutation in homozygosity in a male pseudohermaphrodite with labial scrotal folds, microphallus, chordee, and fourth degree hypospadias. The patient was the child of nonconsanguineous Taiwanese parents. (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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Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. | Lutfallah C | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12050224 |
A new insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency. | Simard J | Endocrine research | 2000 | PMID: 11196452 |
Genotyping of the type II 3beta-hydroxysteroid dehydrogenase gene (HSD3B2) in women with hirsutism and elevated ACTH-stimulated delta(5)-steroids. | Marui S | Fertility and sterility | 2000 | PMID: 10973654 |
Characterization of two novel homozygous missense mutations involving codon 6 and 259 of type II 3beta-hydroxysteroid dehydrogenase (3betaHSD) gene causing, respectively, nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder. | Zhang L | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10770215 |
New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. | Moisan AM | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10599696 |
Molecular analysis of type II 3 beta-hydroxysteroid dehydrogenase gene in Japanese patients with classical 3 beta-hydroxysteroid dehydrogenase deficiency. | Tajima T | Human molecular genetics | 1995 | PMID: 7633460 |
Text-mined citations for rs80358221 ...
HelpRecord last updated Apr 20, 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.