ClinVar Genomic variation as it relates to human health
NM_001128590.1(CYP21A2):c.-113G>A
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_001128590.1(CYP21A2):c.-113G>A
Variation ID: 987867 Accession: VCV000987867.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.33 6: 32038310 (GRCh38) [ NCBI UCSC ] 6: 32006087 (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 Dec 7, 2020 May 13, 2023 Mar 16, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000006.12:32038309:G: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.
The Genome Aggregation Database (gnomAD) 0.00251
1000 Genomes Project 30x 0.00515
- 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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CYP21A2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
17 | 331 | |
LOC106780800 | - | - | - |
GRCh38 GRCh38 |
- | 287 |
LOC110631417 | - | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 |
- | 22 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2023 | RCV001269258.11 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001293784.11 |
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
(Mar 16, 2023)
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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: SCV001448586.2
First in ClinVar: Dec 07, 2020 Last updated: May 13, 2023 |
Comment:
Variant summary: CYP21A2 c.-113G>A is located in the untranscribed region upstream of the CYP21A2 gene region. The variant allele was found at a frequency of … (more)
Variant summary: CYP21A2 c.-113G>A is located in the untranscribed region upstream of the CYP21A2 gene region. The variant allele was found at a frequency of 0.0025 in 150840 control chromosomes, predominantly at a frequency of 0.0069 within the African or African-American subpopulation in the gnomAD v3.1.2 database, including 2 homozygotes. This variant frequency in the African or African-American subpopulation is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP21A2 causing Congenital adrenal hyperplasia phenotype (0.002), suggesting that the variant is benign. However, c.-113G>A has been reported in the literature, most often in conjunction with other promoter variants (i.e. -126C>T, -110T>C and -103A>G), in compound heterozygous individuals affected with Congenital Adrenal Hyperplasia, including classic and non-classic forms (e.g. Araujo_2007, Jeske_2009, New_2013, Xu C_2019, Xu J_2019, Wan_2023). These data indicate that the variant is very likely to be associated with disease. Homozygous occurrences of two (c.[-126C>T;-113G>A]) or four changes (c.[-126C>T;-113G>A;-110T>C;-103A>G]) segregating together in the promoter region have been reported in multiple individuals affected with non-classic adrenal hyperplasia as well as one hyperandrogenic individual suspected to be homozygous or heterozygous for NC 21-OH deficiency (Blanche_1997, Carriere_2023, Wan_2023). The promoter variants c.-126C>T, c.-113G>A, c.-110T>C, and c.-103A>G are normally present in the CYP21A2 pseudogene (CYP21A1P) promoter region and cause the pseudogene to have considerably lower transcription activity when compared with the active CYP21A2 gene (Chin_1998). Approximately, 70% of CYP21A2 disease-causing variants are CYP21A1P-derived variants due to gene conversions, the transfer of inactive pseudogene into the active CYP21A2 gene. Experimental evidence evaluating an impact of the c.-113G>A variant specifically, demonstrated an 80% decrease in transcription activity and a lower binding capacity to nuclear factors (Chin_1998, Araujo_2007). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. European Molecular Genetics Quality Network (EMQN) best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency, describe the variant as definitely pathogenic for nonclassic phenotype. Nonetheless, they state that promoter variants could result in classic as well as nonclassic CAH and/or could modify the phenotype in patients with other variants. However, due to that lack of information on patient data the clinical relevance of promoter sequence variants is unclear and interpretation therefore remains difficult (Baumgartner-Parzer_2020). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV001482477.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant present in the untranscribed (UTR) region of the CYP21A2 gene c.-113G>A (NM_000500.7). This variant was observed in a proband with increased level of … (more)
This variant present in the untranscribed (UTR) region of the CYP21A2 gene c.-113G>A (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (>266.9 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant has previously been reported for congenital adrenal hyperplasia (Araujo RS et al., 2007 PMID: 17666484, Jeske YW et al., 2009 PMID: 19449670, Chin kk et al., 1998 PMID: 9518489, Xu C et al., 2019 PMID: 30968594) (less)
Indication for testing: Increased level of 17-OHP enzyme (>266.9 nmol/L)
Ethnicity/Population group: Asian
Geographic origin: India
Testing laboratory: GTRL000507720
Testing laboratory interpretation: Likely pathogenic
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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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Fertility and pregnancy outcomes in women with nonclassic 21-hydroxylase deficiency. | Carrière C | Clinical endocrinology | 2023 | PMID: 36325983 |
Nonclassic Adrenal Hyperplasia (NCAH) due to 21-hydroxylase deficiency: A cohort of 78 patients. | Wan Z | The Journal of steroid biochemistry and molecular biology | 2023 | PMID: 36167262 |
Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children. | Tolba A | Frontiers in genetics | 2022 | PMID: 35309130 |
CYP21A2 mutations in pediatric patients with congenital adrenal hyperplasia in Costa Rica. | Umaña-Calderón A | Molecular genetics and metabolism reports | 2021 | PMID: 33604243 |
EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. | Baumgartner-Parzer S | European journal of human genetics : EJHG | 2020 | PMID: 32616876 |
Identification of novel and rare CYP21A2 variants in Chinese patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Xu J | Clinical biochemistry | 2019 | PMID: 30995443 |
Genotype-phenotype correlation study and mutational and hormonal analysis in a Chinese cohort with 21-hydroxylase deficiency. | Xu C | Molecular genetics & genomic medicine | 2019 | PMID: 30968594 |
Comprehensive genotyping of Turkish women with hirsutism. | Polat S | Journal of endocrinological investigation | 2019 | PMID: 30811025 |
Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. | New MI | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23359698 |
21-hydroxylase genotyping in Australasian patients with congenital adrenal hyperplasia. | Jeske YW | Journal of pediatric endocrinology & metabolism : JPEM | 2009 | PMID: 19449670 |
p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency. | Menassa R | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18319307 |
Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. | Araújo RS | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17666484 |
Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutation. | Araujo RS | Clinical endocrinology | 2005 | PMID: 15670187 |
The -104G nucleotide of the human CYP21 gene is important for CYP21 transcription activity and protein interaction. | Chin KK | Nucleic acids research | 1998 | PMID: 9518489 |
Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women. | Blanché H | Human genetics | 1997 | PMID: 9385370 |
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Text-mined citations for rs1246774295 ...
HelpRecord last updated Jun 02, 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.