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)). In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. This variant has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). In some published literature, this variant is referred to as Pro30Leu or *8. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown this variant significantly reduces enzymatic activity (PMID: 20080860, 23927611, 24953648, 28539365).
ClinVar Genomic variation as it relates to human health
NM_000500.9(CYP21A2):c.92C>T (p.Pro31Leu)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000500.9(CYP21A2):c.92C>T (p.Pro31Leu)
Variation ID: 12153 Accession: VCV000012153.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.33 6: 32038514 (GRCh38) [ NCBI UCSC ] 6: 32006291 (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 Oct 2, 2013 Aug 25, 2024 Jul 16, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000500.9:c.92C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000491.4:p.Pro31Leu missense NM_001128590.4:c.92C>T NP_001122062.3:p.Pro31Leu missense NM_001368143.2:c.-333C>T 5 prime UTR NM_001368144.2:c.-243C>T 5 prime UTR NC_000006.12:g.32038514C>T NC_000006.11:g.32006291C>T NG_007941.3:g.5210C>T NG_045215.1:g.743C>T NG_055451.1:g.5190C>T LRG_829:g.5210C>T LRG_829t1:c.92C>T LRG_829p1:p.Pro31Leu - Protein change
- P31L
- Other names
-
P30L
- Canonical SPDI
- NC_000006.12:32038513: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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00055
1000 Genomes Project 30x 0.00078
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CYP21A2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
23 | 354 | |
| LOC106780800 | - | - | - |
GRCh38 GRCh38 |
- | 304 |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 16, 2023 | RCV000012938.13 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2023 | RCV000711390.15 |
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
(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: SCV000893710.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Mar 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000841753.4
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)). In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. This variant has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). In some published literature, this variant is referred to as Pro30Leu or *8. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown this variant significantly reduces enzymatic activity (PMID: 20080860, 23927611, 24953648, 28539365). (less)
|
|
|
Pathogenic
(Jul 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086586.1
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 congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type 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 leucine. (I) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 77 heterozygotes, 1 homozygote). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to cause 30-60% loss of 21-hydroxylase enzymatic activity (PMID: 26804566). (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)
|
|
|
Pathogenic
(Dec 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194148.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for … (more)
NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23142378, 16427797, 23359698, 1644925, 2072928 and 9215318. Classification of NM_000500.7(CYP21A2):c.92C>T(P31L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Feb 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449882.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002189414.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). 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 classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2072928, 23142378, 23359698, 26804566, 31446012). 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 P30L. ClinVar contains an entry for this variant (Variation ID: 12153). 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: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046435.3
First in ClinVar: Jan 01, 2022 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been … (more)
In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been seen in many affected individuals with either a salt-wasting or simple virilizing phenotype as a result of being carried in combination with different pathogenic variants (PMIDs: 22629504 (2012), 26425475 (2015), and 27041116 (2016)). Functional studies have shown this variant significantly reduces enzymatic activity (PMIDs: 20080860 (2010), 23927611 (2014), 24953648 (2015), and 28539365 (2017)). The variant under the control of the CYP21A2 gene promoter has been reported to cause a less severe phenotype than under the control of the CYP21A pseudogene promoter (PMID: 15670187 (2005)). The frequency of this variant in the general population, 0.00059 (14/23690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197681.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jul 28, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000590901.1
First in ClinVar: Aug 21, 2017 Last updated: Aug 21, 2017 |
Comment:
This variant has been reported in 1000 genomes database, dbSNP(rs9378251) and HGMD. The in silico prediction of this variant is disease-causing by MutationTaster.
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hindu/Gujarati
Geographic origin: India
Method: The exon-intron boundaries of the CYP21A2 gene were bi-directionally sequenced using an automated sequencer.
|
|
|
Pathogenic
(Jul 01, 1997)
|
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: SCV000033179.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2018 |
Comment on evidence:
The mild nonclassic form of steroid 21-hydroxylase deficiency (201910) is one of the most common autosomal recessive disorders in humans, occurring in almost 1% of … (more)
The mild nonclassic form of steroid 21-hydroxylase deficiency (201910) is one of the most common autosomal recessive disorders in humans, occurring in almost 1% of Caucasians and about 3% of Ashkenazi Jews. Many patients with this disorder carry a val281-to-leu (V281L) mutation in the CYP21 gene. This and most other mutations causing 21-hydroxylase deficiency are normally present in the CYP21P pseudogene and have presumably been transferred to CYP21 by gene conversion. To identify other potential nonclassic alleles, Tusie-Luna et al. (1991) used recombinant vaccinia virus to express 2 mutant enzymes carrying the mutations pro30 to leu (normally present in CYP21P) and ser268 to thr (considered a normal polymorphism of CYP21; see 613815.0005). Whereas the activity of the protein carrying the ser-to-thr mutation was indeed indistinguishable from the wildtype, the enzyme with the pro-to-leu substitution had 60% of the wildtype activity for 17-hydroxyprogesterone and about 30% of normal activity for progesterone when assayed in intact cells. Proline-30 is conserved in many microsomal P450 enzymes and may be important for proper orientation of the enzyme with respect to the amino-terminal transmembrane segment. The pro30-to-leu mutation was present in 5 of 18 patients with nonclassic 21-hydroxylase deficiency. Tajima et al. (1997) observed the P30L mutation in 1 allele in 3 of 4 patients (2 sibs and 2 unrelated newborns) with nonclassic CAH in Japan. (less)
|
|
|
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: SCV000086805.2
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
|
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Comment:
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 of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type 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 leucine. (I) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 77 heterozygotes, 1 homozygote). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to cause 30-60% loss of 21-hydroxylase enzymatic activity (PMID: 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23142378, 16427797, 23359698, 1644925, 2072928 and 9215318. Classification of NM_000500.7(CYP21A2):c.92C>T(P31L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). 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 classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2072928, 23142378, 23359698, 26804566, 31446012). 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 P30L. ClinVar contains an entry for this variant (Variation ID: 12153). 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: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic.
Comment:
In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been seen in many affected individuals with either a salt-wasting or simple virilizing phenotype as a result of being carried in combination with different pathogenic variants (PMIDs: 22629504 (2012), 26425475 (2015), and 27041116 (2016)). Functional studies have shown this variant significantly reduces enzymatic activity (PMIDs: 20080860 (2010), 23927611 (2014), 24953648 (2015), and 28539365 (2017)). The variant under the control of the CYP21A2 gene promoter has been reported to cause a less severe phenotype than under the control of the CYP21A pseudogene promoter (PMID: 15670187 (2005)). The frequency of this variant in the general population, 0.00059 (14/23690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant has been reported in 1000 genomes database, dbSNP(rs9378251) and HGMD. The in silico prediction of this variant is disease-causing by MutationTaster.
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. |
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 variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. This variant has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). In some published literature, this variant is referred to as Pro30Leu or *8. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown this variant significantly reduces enzymatic activity (PMID: 20080860, 23927611, 24953648, 28539365).
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 of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type 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 leucine. (I) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 77 heterozygotes, 1 homozygote). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to cause 30-60% loss of 21-hydroxylase enzymatic activity (PMID: 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23142378, 16427797, 23359698, 1644925, 2072928 and 9215318. Classification of NM_000500.7(CYP21A2):c.92C>T(P31L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). 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 classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2072928, 23142378, 23359698, 26804566, 31446012). 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 P30L. ClinVar contains an entry for this variant (Variation ID: 12153). 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: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic.
Comment:
In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been seen in many affected individuals with either a salt-wasting or simple virilizing phenotype as a result of being carried in combination with different pathogenic variants (PMIDs: 22629504 (2012), 26425475 (2015), and 27041116 (2016)). Functional studies have shown this variant significantly reduces enzymatic activity (PMIDs: 20080860 (2010), 23927611 (2014), 24953648 (2015), and 28539365 (2017)). The variant under the control of the CYP21A2 gene promoter has been reported to cause a less severe phenotype than under the control of the CYP21A pseudogene promoter (PMID: 15670187 (2005)). The frequency of this variant in the general population, 0.00059 (14/23690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant has been reported in 1000 genomes database, dbSNP(rs9378251) and HGMD. The in silico prediction of this variant is disease-causing by MutationTaster.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland - experience of a clinical center. | Kurzyńska A | Hormones (Athens, Greece) | 2022 | PMID: 35079965 |
| Comprehensive Genetic Testing of CYP21A2: A Retrospective Analysis in Patients with Suspected Congenital Adrenal Hyperplasia. | Nan MN | Journal of clinical medicine | 2021 | PMID: 33809035 |
| Genotype and clinical outcomes in children with congenital adrenal hyperplasia. | Yoon JY | Pediatrics international : official journal of the Japan Pediatric Society | 2021 | PMID: 32965796 |
| Genetic characterization of a large cohort of Argentine 21-hydroxylase Deficiency. | Fernández CS | Clinical endocrinology | 2020 | PMID: 32289882 |
| 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 |
| Analysis of phenotypes and genotypes in 84 patients with 21-Hydroxylase deficiency in southern China. | Hou L | Steroids | 2019 | PMID: 31446012 |
| 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 |
| CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort. | Santos-Silva R | Hormone research in paediatrics | 2019 | PMID: 30889569 |
| Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia. | Wang C | The Journal of biological chemistry | 2017 | PMID: 28539365 |
| Molecular genetic analysis in 93 patients and 193 family members with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia. | Dumic KK | The Journal of steroid biochemistry and molecular biology | 2017 | PMID: 27041116 |
| 21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations. | Wang R | Steroids | 2016 | PMID: 26804566 |
| 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. | Adam MP | - | 2016 | PMID: 20301350 |
| Clinical profile and inheritance pattern of CYP21A2 gene mutations in patients with classical congenital adrenal hyperplasia from 10 families. | Yadav S | Indian journal of endocrinology and metabolism | 2015 | PMID: 26425475 |
| CYP21A2 mutation analysis in Korean patients with congenital adrenal hyperplasia using complementary methods: sequencing after long-range PCR and restriction fragment length polymorphism analysis with multiple ligation-dependent probe amplification assay. | Hong G | Annals of laboratory medicine | 2015 | PMID: 26206692 |
| Gonadotropin releasing hormone analog treatment in children with congenital adrenal hyperplasia complicated by central precocious puberty. | Güven A | Hormones (Athens, Greece) | 2015 | PMID: 25553759 |
| 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 |
| Functional consequences of a novel point mutation in the CYP21A2 gene identified in a Chinese Han patient with nonclassic 21-hydroxylase deficiency. | Chu X | Clinical endocrinology | 2014 | PMID: 23927611 |
| Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. | Xu Z | The Journal of molecular diagnostics : JMD | 2013 | PMID: 24071710 |
| 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 |
| Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation. | Toraman B | Gene | 2013 | PMID: 23142378 |
| Reverse-hybridization assay for rapid detection of common CYP21A2 mutations in dried blood spots from newborns with elevated 17-OH progesterone. | Németh S | Clinica chimica acta; international journal of clinical chemistry | 2012 | PMID: 22985688 |
| Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia. | Marumudi E | Indian journal of endocrinology and metabolism | 2012 | PMID: 22629504 |
| Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. | Chen W | Clinical chemistry | 2012 | PMID: 22156666 |
| 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 |
| Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. | Ghizzoni L | European journal of endocrinology | 2011 | PMID: 21646284 |
| Ethnic disparity in 21-hydroxylase gene mutations identified in Pakistani congenital adrenal hyperplasia patients. | Khan AH | BMC endocrine disorders | 2011 | PMID: 21329531 |
| Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia. | Vrzalová Z | European journal of medical genetics | 2011 | PMID: 20970527 |
| 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 |
| Molecular defects of the CYP21A2 gene in Greek-Cypriot patients with congenital adrenal hyperplasia. | Skordis N | Hormone research in paediatrics | 2011 | PMID: 20838032 |
| Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. | Vrzalová Z | International journal of molecular medicine | 2010 | PMID: 20818501 |
| Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify 'apparently mild' CYP21A2 alleles which associate neonatal salt-wasting disease. | Ezquieta B | Prenatal diagnosis | 2010 | PMID: 20661889 |
| Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier. | Tardy V | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20080860 |
| Comparing the Southern blot method and polymerase chain reaction product analysis for chimeric RCCX detection in CYP21A2 deficiency. | Lee HH | Analytical biochemistry | 2010 | PMID: 19961824 |
| 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 |
| Application of the DHPLC method for mutational detection of the CYP21A2 gene in congenital adrenal hyperplasia. | Tsai LP | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19778530 |
| A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form. | Concolino P | BMC medical genetics | 2009 | PMID: 19624807 |
| High frequency of Q318X mutation in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in northeast Brazil. | Campos VC | Arquivos brasileiros de endocrinologia e metabologia | 2009 | PMID: 19347184 |
| Variations in the promoter of CYP21A2 gene identified in a Chinese patient with simple virilizing form of 21-hydroxylase deficiency. | Zhang HJ | Clinical endocrinology | 2009 | PMID: 18702679 |
| Low frequency of the CYP21A2 deletion in ethnic Chinese (Taiwanese) patients with 21-hydroxylase deficiency. | Lee HH | Molecular genetics and metabolism | 2008 | PMID: 18039588 |
| Predisposition for de novo gene aberrations in the offspring of mothers with a duplicated CYP21A2 gene. | Baumgartner-Parzer SM | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17164306 |
| High variability in CYP21A2 mutated alleles in Spanish 21-hydroxylase deficiency patients, six novel mutations and a founder effect. | Loidi L | Clinical endocrinology | 2006 | PMID: 16487445 |
| CYP21A2 mutations in Portuguese patients with congenital adrenal hyperplasia: identification of two novel mutations and characterization of four different partial gene conversions. | Friães A | Molecular genetics and metabolism | 2006 | PMID: 16427797 |
| 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 |
| Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia. | Barbaro M | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15126570 |
| Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. | Torres N | Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas | 2003 | PMID: 14502362 |
| Characterization of the CYP21 gene 5' flanking region in patients affected by 21-OH deficiency. | Bobba A | Human mutation | 2000 | PMID: 10790214 |
| Molecular basis of nonclassical steroid 21-hydroxylase deficiency detected by neonatal mass screening in Japan. | Tajima T | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9215318 |
| Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Speiser PW | The Journal of clinical investigation | 1992 | PMID: 1644925 |
| A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic steroid 21-hydroxylase deficiency allele. | Tusie-Luna MT | Molecular endocrinology (Baltimore, Md.) | 1991 | PMID: 2072928 |
| Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. | Tusie-Luna MT | The Journal of biological chemistry | 1990 | PMID: 2249999 |
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Text-mined citations for rs9378251 ...
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Record last updated Sep 29, 2024
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