ClinVar Genomic variation as it relates to human health
NM_000500.9(CYP21A2):c.1360C>T (p.Pro454Ser)
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
-
NM_000500.9(CYP21A2):c.1360C>T (p.Pro454Ser)
Variation ID: 12159 Accession: VCV000012159.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.33 6: 32041006 (GRCh38) [ NCBI UCSC ] 6: 32008783 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 23, 2024 Dec 16, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000500.9:c.1360C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000491.4:p.Pro454Ser missense NM_001128590.4:c.1270C>T NP_001122062.3:p.Pro424Ser missense NM_001368143.2:c.955C>T NP_001355072.1:p.Pro319Ser missense NM_001368144.2:c.955C>T NP_001355073.1:p.Pro319Ser missense NC_000006.12:g.32041006C>T NC_000006.11:g.32008783C>T NG_007941.3:g.7702C>T NG_008337.2:g.73369G>A NG_045215.1:g.3235C>T LRG_829:g.7702C>T LRG_829t1:c.1360C>T LRG_829p1:p.Pro454Ser - Protein change
- P454S, P424S, P319S
- Other names
- P453S
- Canonical SPDI
- NC_000006.12:32041005:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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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0.00180 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00180
Exome Aggregation Consortium (ExAC) 0.00228
The Genome Aggregation Database (gnomAD), exomes 0.00460
The Genome Aggregation Database (gnomAD) 0.00530
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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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CYP21A2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
17 | 329 | |
LOC106780800 | - | - | - |
GRCh38 GRCh38 |
- | 286 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000012943.18 | |
Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Aug 4, 2023 | RCV000711371.26 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 26, 2021 | RCV002288483.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 16, 2023 | RCV003924827.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 19, 2022 | RCV003985261.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251458.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The CYP21A2 c.1360C>T (p.P454S) missense variant has been reported in individuals with nonclassical late-onset 21-hydroxylase deficiency (PMID: 1406699; 18381579; 1496017).
Number of individuals with the variant: 2
|
|
Pathogenic
(May 19, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449847.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 13
|
|
Pathogenic
(Jun 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556234.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: CYP21A2 c.1360C>T (p.Pro454Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CYP21A2 c.1360C>T (p.Pro454Ser) results in a non-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 0.0046 in 137706 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CYP21A2 causing Congenital Adrenal Hyperplasia/Non-Classic (0.0046 vs 0.032), allowing no conclusion about variant significance. c.1360C>T has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia. 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%-<30% of normal activity (Helmberg_1992, Nikoshkov_1997, Soardi_2008). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768107.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
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 nonclassic type hyperandrogenism due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 757 heterozygotes, 2 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is regarded as definitely pathogenic by EMQN (PMID: 32616876) and is associated to the nonclassic type of hyperandrogenism due to 21-hydroxylase deficiency (ClinVar, LOVD, PMID: 31586465). (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
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002126037.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 454 of the CYP21A2 protein (p.Pro454Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 454 of the CYP21A2 protein (p.Pro454Ser). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 1406699, 10720040, 12222711, 12887291, 21444649, 21843885, 22270556, 23073904, 31333583, 32966723). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as P453S. ClinVar contains an entry for this variant (Variation ID: 12159). 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 not expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 18381579, 24953648, 30968594). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835070.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics Inc
Accession: SCV000841733.4
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2024 |
Comment:
Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of … (more)
Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is reported to associate with non-classic congenital adrenal hyperplasia (CAH). This variant is also referred to as p.Pro453Ser (P453S) in published literature. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in reduced enzymatic activity (PMID: 24953648). (less)
|
|
Pathogenic
(Aug 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018116.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Aug 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV004801697.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
ACMG categories: PS3,PS4,PM1,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Adrenogenital syndrome (present)
Age: 30-39 years
Sex: female
Tissue: blood
|
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Pathogenic
(Jul 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000494248.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Comment:
The c.1360C>T (p.Pro454Ser) missense variant in the CYP21A2 gene has been previously reported in multiple individuals affected with 21-OHD CAH and is associated with the … (more)
The c.1360C>T (p.Pro454Ser) missense variant in the CYP21A2 gene has been previously reported in multiple individuals affected with 21-OHD CAH and is associated with the non-classic form of this disorder (Owerbach et al., 1992; Vigliani and Buster, 2012; Skordis et al., 2015; Neocleous et al., 2014). This variant is present significantly more frequently in affected individuals than controls (OR = 18; 95%CI = 2.37-136), and is absent or reported at low frequency in the population databases (Exome Sequencing Project [ESP]; 1000 Genomes=0.6%; ExAC=0.88%). Furthermore, in vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (Nikoshkov et al., 1997, Barbaro et al., 2015). Structural studies predict that Pro454 is positioned within a hydrophobic pocket, and that the p.Pro454Ser variant will disrupt the hydrophobicity of this region (Haider et al., 2013). In addition, Emory Genetics Laboratory has classified this variant as Pathogenic. Pathogenic variants in the CYP21A2 gene are the only known cause of 21-OHD CAH. Therefore, this collective evidence supports the classification of the c.1360C>T (p.Pro454Ser) as a Pathogenic variant for congenital adrenal hyperplasia. We have confirmed this finding in our laboratory using Sanger sequencing. (less)
|
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Pathogenic
(Dec 29, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224844.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893714.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Jun 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501425.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519469.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572784.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.453%. Missense changes are a common disease-causing mechanism. In … (more)
It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.453%. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.45; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012159). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cryptorchidism (present) , Hypospadias (present) , Gynecomastia (present) , Delayed puberty (present)
|
|
Pathogenic
(Jul 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital lipoid adrenal hyperplasia due to STAR deficency
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579439.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009127.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Pathogenic
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004021289.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047337.3
First in ClinVar: Jan 01, 2022 Last updated: Jan 06, 2024 |
Comment:
The variant seen in patients with salt-wasting phenotype (PMID: 12788866 (2003)) and simple virilizing phenotype (PMID: 18381579 (2008)). Functional evidence suggests that this variant may … (more)
The variant seen in patients with salt-wasting phenotype (PMID: 12788866 (2003)) and simple virilizing phenotype (PMID: 18381579 (2008)). Functional evidence suggests that this variant may impact protein function. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and have phenotype known to be consistent with disease. (less)
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Pathogenic
(Dec 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
CYP21A2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004746571.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CYP21A2 c.1360C>T variant is predicted to result in the amino acid substitution p.Pro454Ser. This variant is associated with autosomal recessive non-classic congenital adrenal hyperplasia … (more)
The CYP21A2 c.1360C>T variant is predicted to result in the amino acid substitution p.Pro454Ser. This variant is associated with autosomal recessive non-classic congenital adrenal hyperplasia (CAH) (also known as P453S; New et al. 2006. PubMed ID: 16912124; Nikoshkov et al. 1997. PubMed ID: 8989258; Soardi et al. 2008. PubMed ID: 18381579). This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142355.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000500.7:c.1360C>T in the CYP21A2 gene has an allele frequency of 0.009 in European (non-Finnish) subpopulation in the gnomAD database. The c.1360C>T (p.Pro454Ser) missense variant in … (more)
NM_000500.7:c.1360C>T in the CYP21A2 gene has an allele frequency of 0.009 in European (non-Finnish) subpopulation in the gnomAD database. The c.1360C>T (p.Pro454Ser) missense variant in the CYP21A2 gene, also known as p.Pro453Ser in literatures, has been previously found in 46.2% of 13 unrelated NC-CAH patients, but only 7.7% and 3.6% of salt-wasting CAH patients and blood donors, respectively (PMID: 1406699). In vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (PMID: 24953648). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationTaster and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP3, PS4, PS3. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740291.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953135.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jun 01, 2008)
|
no assertion criteria provided
Method: literature only
|
ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, NONCLASSIC TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033185.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Using PCR in a study of the structure of the CYP21 gene in 13 unrelated nonclassic steroid 21-hydroxylase deficiency (201910) patients, 3 affected sibs, and … (more)
Using PCR in a study of the structure of the CYP21 gene in 13 unrelated nonclassic steroid 21-hydroxylase deficiency (201910) patients, 3 affected sibs, and 55 blood donors, Owerbach et al. (1992) found the val281-to-leu (613815.0002) and pro30-to-leu (613815.0004) mutations, as well as a pro453-to-ser (P453S) mutation in exon 10. The P453S mutation was identified in 46.2% of unrelated nonclassic CAH patients, but only 7.7% and 3.6% of salt-wasting CAH patients and blood donors, respectively. In contrast to the other 2 'nonclassic' mutations, pro453 to ser had not been detected in the CYP21 pseudogene and, therefore, probably had not arisen by gene conversion. Soardi et al. (2008) found that P453S and another nonclassic mutation, H62L (613815.0034), had a synergistic interaction. When the mutant proteins were expressed together in COS cells, the activity of the enzyme was reduced to 4.1% and 2.3% toward 17OHP and progesterone, respectively. Two unrelated patients who both carried P453S+H62L on the paternal allele had a mild simple virilizing phenotype. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808018.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967148.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086792.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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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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Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. | Merke DP | The New England journal of medicine | 2020 | PMID: 32966723 |
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 |
21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. | Turan I | European journal of medical genetics | 2020 | PMID: 31586465 |
The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency. | Pignatelli D | Frontiers in endocrinology | 2019 | PMID: 31333583 |
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 |
Phenotype heterogeneity of congenital adrenal hyperplasia due to genetic mosaicism and concomitant nephrogenic diabetes insipidus in a sibling. | Kor Y | BMC medical genetics | 2018 | PMID: 29996815 |
A genetic epidemiology study of congenital adrenal hyperplasia in Italy. | Gialluisi A | Clinical genetics | 2018 | PMID: 28644547 |
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. | Adam MP | - | 2016 | PMID: 20301350 |
Genetic defects of the CYP21A2 gene in girls with premature adrenarche. | Skordis N | Journal of endocrinological investigation | 2015 | PMID: 25481255 |
In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia. | Barbaro M | Clinical endocrinology | 2015 | PMID: 24953648 |
Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations. | Neocleous V | Indian journal of endocrinology and metabolism | 2014 | PMID: 25538881 |
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. | Haider S | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23359706 |
Comprehensive genetic analysis and structural characterization of CYP21A2 mutations in CAH patients. | Carvalho B | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2012 | PMID: 23073904 |
Nonclassic 21-hydroxylase deficiency presenting as endometrial hyperplasia with uterine bleeding in a 67-year-old woman. | Vigliani MB | Fertility and sterility | 2012 | PMID: 22270556 |
Mutation analysis of the CYP21A2 gene in the Iranian population. | Rabbani B | Genetic testing and molecular biomarkers | 2012 | PMID: 22017335 |
Infertility reversed by glucocorticoids and full-term pregnancy in a couple with previously undiagnosed nonclassic congenital adrenal hyperplasia. | Trakakis E | Fertility and sterility | 2011 | PMID: 21843885 |
Endocrine profile and phenotype-genotype correlation in unrelated patients with non-classical congenital adrenal hyperplasia. | Skordis N | Clinical biochemistry | 2011 | PMID: 21635882 |
Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families. | Nandagopal R | European journal of endocrinology | 2011 | PMID: 21444649 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Finkielstain GP | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 20926536 |
CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. | Baş F | Journal of clinical research in pediatric endocrinology | 2009 | PMID: 21274396 |
Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. | Bidet M | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19208730 |
Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients. | Soardi FC | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18381579 |
Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease. | Dolzan V | European journal of endocrinology | 2003 | PMID: 12887291 |
Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management. | Pinto G | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12788866 |
Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations. | Ezquieta B | Acta paediatrica (Oslo, Norway : 1992) | 2002 | PMID: 12222711 |
Novel mutations in CYP21 detected in individuals with hyperandrogenism. | Lajić S | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12050257 |
Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation. | Baumgartner-Parzer SM | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11600539 |
Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Deneux C | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11232002 |
Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. | Krone N | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10720040 |
Mutation analysis in patients with congenital adrenal hyperplasia in the Spanish population: identification of putative novel steroid 21-hydroxylase deficiency alleles associated with the classic form of the disease. | Lobato MN | Human heredity | 1999 | PMID: 10364682 |
High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche. | Dacou-Voutetakis C | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10323382 |
Synergistic effect of partially inactivating mutations in steroid 21-hydroxylase deficiency. | Nikoshkov A | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 8989258 |
Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations. | Wedell A | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1496017 |
R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions. | Helmberg A | Molecular endocrinology (Baltimore, Md.) | 1992 | PMID: 1406709 |
Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency. | Owerbach D | Molecular endocrinology (Baltimore, Md.) | 1992 | PMID: 1406699 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2 | - | - | - | - |
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Text-mined citations for rs6445 ...
HelpRecord last updated Mar 23, 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.