Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012150, PMID:3257825, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24671123, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, PP3_P). A missense variant is a common mechanism associated with Hyperandrogenism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000577, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn)
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.
(22)
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.
Conflicting classifications of pathogenicity
Pathogenic(17); Uncertain significance(1)
Pathogenic(17); Uncertain significance(1)
22
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of 2 Genotypes
- Identifiers
-
NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn)
Variation ID: 12150 Accession: VCV000012150.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.33 6: 32039426 (GRCh38) [ NCBI UCSC ] 6: 32007203 (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 Aug 25, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000500.9:c.518T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000491.4:p.Ile173Asn missense NM_000500.2:c.518T>A NM_001128590.4:c.428T>A NP_001122062.3:p.Ile143Asn missense NM_001368143.2:c.113T>A NP_001355072.1:p.Ile38Asn missense NM_001368144.2:c.113T>A NP_001355073.1:p.Ile38Asn missense NC_000006.12:g.32039426T>A NC_000006.11:g.32007203T>A NG_007941.3:g.6122T>A NG_008337.2:g.74949A>T NG_045215.1:g.1655T>A LRG_829:g.6122T>A LRG_829t1:c.518T>A LRG_829p1:p.Ile173Asn - Protein change
- I173N, I143N, I38N
- Other names
-
I172N
rs6475
- Canonical SPDI
- NC_000006.12:32039425:T:A
-
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.
-
0.00080 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00048
1000 Genomes Project 0.00080
The Genome Aggregation Database (gnomAD) 0.00117
1000 Genomes Project 30x 0.00219
- 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (13) |
criteria provided, conflicting classifications
|
Apr 4, 2024 | RCV000012933.24 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2014 | RCV000622562.2 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2023 | RCV000711382.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 15, 2023 | RCV003226157.1 |
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
(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: SCV000893712.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 03, 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: SCV002059027.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012150, PMID:3257825, PS1_S). Functional … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012150, PMID:3257825, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24671123, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, PP3_P). A missense variant is a common mechanism associated with Hyperandrogenism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000577, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Congenital adrenal hyperplasia (present) , Stage 5 chronic kidney disease (present) , Focal segmental glomerulosclerosis (present)
|
|
|
Pathogenic
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: no
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784271.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: no
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784270.2
First in ClinVar: Oct 01, 2013 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital adrenal hyperplasia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922699.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: CYP21A2 c.518T>A (p.Ile173Asn, aka. I172N) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict … (more)
Variant summary: CYP21A2 c.518T>A (p.Ile173Asn, aka. I172N) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 249434 control chromosomes (gnomAD). c.518T>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of Congenital Adrenal Hyperplasia (see e.g. Amor_1988, Dolzan_2005, Simonetti_2018, Xu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced enzyme activity (e.g. Tusie-Luna_1990, Chiou_1990, Xu_2019). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000841745.5
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. This variant is also referred to as p.Ile172Asn 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. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123). (less)
|
|
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Pathogenic
(Mar 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018112.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 17, 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
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767610.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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_v1.3.2, 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. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (181 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytochrome P450 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in many patients with congenital adrenal hyperplasia (ClinVar, HGMD, PMID: 3257825, PMID: 31586465). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Jul 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854779.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883113.1
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018 |
|
|
|
Pathogenic
(Dec 20, 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: SCV001194146.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000500.7(CYP21A2):c.518T>A(I173N) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for … (more)
NM_000500.7(CYP21A2):c.518T>A(I173N) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 24667412, 21098686, 24671123, 23359698, 22270556, 19750867 and 3257825. Classification of NM_000500.7(CYP21A2):c.518T>A(I173N) 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)
|
|
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Pathogenic
(Nov 09, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449827.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 43
|
|
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Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: yes
Allele origin:
germline
|
Provincial Medical Genetics Program of British Columbia, University of British Columbia
Accession: SCV002320854.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Sex: female
|
|
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Pathogenic
(Sep 07, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740722.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Congenital adrenal hyperplasia (present) , Parkinsonism (present) , Autistic disorder of childhood onset (present) , Dystonia (present) , Tremor (present) , Hyperreflexia (present) , Chorea … (more)
Congenital adrenal hyperplasia (present) , Parkinsonism (present) , Autistic disorder of childhood onset (present) , Dystonia (present) , Tremor (present) , Hyperreflexia (present) , Chorea (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) , Movement disorder (present) , Perivascular spaces (present) , Abnormal involuntary eye movements (present) , Parkinsonism (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
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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: SCV003252584.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). 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: 3257825, 8698338, 23359698, 26804566, 30968594). 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 I172N. ClinVar contains an entry for this variant (Variation ID: 12150). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469964.4
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, … (more)
The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of CAH (PMIDs: 3257825 (1988), 17042033 (2006), 21098686 (2011), 23359698 (2013), 31586465 (2020)). In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014)). The frequency of this variant in the general population, 0.0016 (41/25010 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
|
|
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Uncertain significance
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810194.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
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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: SCV005197683.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(-)
|
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
|
Lifecell International Pvt. Ltd
Accession: SCV001482475.2
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant in exon 4 of the CYP21A2 gene results in the amino acid substitution from Isoleucine to Asparagine at codon 173 (p.Ile173Asn) with the … (more)
This variant in exon 4 of the CYP21A2 gene results in the amino acid substitution from Isoleucine to Asparagine at codon 173 (p.Ile173Asn) with the sequence change of c.518T>A (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (86.9 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.000798722 and 0.0005771 in the 1000G database and gnomAD database respectively. The nucleotide is predicted conserved by GERP++ and PhyloP and the in-silico predictions by MutationTaster and SIFT are damaging. This variant lies in the p450 domain of CP21A_HUMAN protein (http://pfam.xfam.org/protein/P08686). This variant (also referred as Ile172Asn) has been previously reported for congenital adrenal hyperplasia (Amor et al., 1988;PMID: 3257825, Speiser et al., 1992;PMID: 1644925, New et al., 2013;PMID: 23359698). Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990;PMID: 2249999, Chiou et al., 1990;PMID: 2303461, Brønstad et al., 2014;PMID: 24671123). (less)
Indication for testing: Decreased level of 17-OHP enzyme (>86.9 nmol/L)
Testing laboratory: GTRL000507720
Testing laboratory interpretation: Pathogenic
|
|
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Pathogenic
(Jul 01, 1997)
|
no assertion criteria provided
Method: literature only
|
ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, CLASSIC TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033174.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Most mutations in the CYP21 gene causing congenital adrenal hyperplasia (201910) are deletions. Amor et al. (1988) reported the cloning and characterization of a nondeleted … (more)
Most mutations in the CYP21 gene causing congenital adrenal hyperplasia (201910) are deletions. Amor et al. (1988) reported the cloning and characterization of a nondeleted mutant CYP21B gene. Codon 172 of the mutant gene was found to be changed from ATC, encoding isoleucine, to AAC, encoding asparagine. This mutation (I172N) is normally present in the CYP21A pseudogene, so that it may have been transferred to the mutant CYP21B gene by gene conversion. Hybridization of oligonucleotide probes corresponding to this and 2 other mutations normally present in CYP21A demonstrated that 4 out of 20 patients carried the codon 172 mutation; in 1 of these patients, the mutation was present as part of a larger gene conversion involving at least exons 3-6. Gene conversion may be a frequent cause of 21-hydroxylase deficiency alleles due to the presence of 6 chi-like sequences (GCTGGGG) in the CYP21 genes and the close proximity of the CYP21A pseudogene, which has several potentially deleterious mutations. Chiou et al. (1990) also found this mutation on 1 allele in a compound heterozygote. Partanen and Campbell (1991) amplified the full-length genomic P450C21 gene by PCR. The ile172-to-asn mutation in exon 4 was demonstrated. This mutation was observed also by Wedell et al. (1992), who referred to it as ILE173ASN. Speiser et al. (1992) found this mutation in 16% of 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The mutation falls into their group B with 2% enzyme activity and a simple virilizing phenotype. Among 127 patients with 21-hydroxylase deficiency in Sweden, Wedell et al. (1994) found that the ile173-to-asn mutation accounted for 20.8% of 186 unrelated chromosomes. (In the same study, the CYP21 gene was completely absent in 29.8% of chromosomes, the val281-to-leu mutation accounted for 5.4%, and the arg356-to-trp mutation accounted for 3.8%. The most frequent nondeletional mutation was the splice mutation in intron 2, which accounted for 27.7% of the chromosomes.) This mutation is found in 28% of all the cases of simple virilizing type (White et al., 1994). To clarify the molecular basis of nonclassic CAH detectable by neonatal screening in Japan, Tajima et al. (1997) identified 2 sibs and 2 unrelated newborns who were diagnosed with probable nonclassic steroid 21-hydroxylase deficiency. The 2 sibs were found to have 1 allele that had 2 mutations, ile172 to asn and arg356 to trp. (less)
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Pathogenic
(Oct 30, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004099489.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
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: SCV000086799.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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Comment:
Comment:
Variant summary: CYP21A2 c.518T>A (p.Ile173Asn, aka. I172N) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 249434 control chromosomes (gnomAD). c.518T>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of Congenital Adrenal Hyperplasia (see e.g. Amor_1988, Dolzan_2005, Simonetti_2018, Xu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced enzyme activity (e.g. Tusie-Luna_1990, Chiou_1990, Xu_2019). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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. This variant is also referred to as p.Ile172Asn 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. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (181 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytochrome P450 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in many patients with congenital adrenal hyperplasia (ClinVar, HGMD, PMID: 3257825, PMID: 31586465). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
NM_000500.7(CYP21A2):c.518T>A(I173N) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 24667412, 21098686, 24671123, 23359698, 22270556, 19750867 and 3257825. Classification of NM_000500.7(CYP21A2):c.518T>A(I173N) 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 isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). 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: 3257825, 8698338, 23359698, 26804566, 30968594). 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 I172N. ClinVar contains an entry for this variant (Variation ID: 12150). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of CAH (PMIDs: 3257825 (1988), 17042033 (2006), 21098686 (2011), 23359698 (2013), 31586465 (2020)). In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014)). The frequency of this variant in the general population, 0.0016 (41/25010 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant in exon 4 of the CYP21A2 gene results in the amino acid substitution from Isoleucine to Asparagine at codon 173 (p.Ile173Asn) with the sequence change of c.518T>A (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (86.9 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.000798722 and 0.0005771 in the 1000G database and gnomAD database respectively. The nucleotide is predicted conserved by GERP++ and PhyloP and the in-silico predictions by MutationTaster and SIFT are damaging. This variant lies in the p450 domain of CP21A_HUMAN protein (http://pfam.xfam.org/protein/P08686). This variant (also referred as Ile172Asn) has been previously reported for congenital adrenal hyperplasia (Amor et al., 1988;PMID: 3257825, Speiser et al., 1992;PMID: 1644925, New et al., 2013;PMID: 23359698). Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990;PMID: 2249999, Chiou et al., 1990;PMID: 2303461, Brønstad et al., 2014;PMID: 24671123).
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:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012150, PMID:3257825, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24671123, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, PP3_P). A missense variant is a common mechanism associated with Hyperandrogenism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000577, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: CYP21A2 c.518T>A (p.Ile173Asn, aka. I172N) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 249434 control chromosomes (gnomAD). c.518T>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of Congenital Adrenal Hyperplasia (see e.g. Amor_1988, Dolzan_2005, Simonetti_2018, Xu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced enzyme activity (e.g. Tusie-Luna_1990, Chiou_1990, Xu_2019). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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. This variant is also referred to as p.Ile172Asn 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. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (181 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytochrome P450 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in many patients with congenital adrenal hyperplasia (ClinVar, HGMD, PMID: 3257825, PMID: 31586465). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
NM_000500.7(CYP21A2):c.518T>A(I173N) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 24667412, 21098686, 24671123, 23359698, 22270556, 19750867 and 3257825. Classification of NM_000500.7(CYP21A2):c.518T>A(I173N) 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 isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). 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: 3257825, 8698338, 23359698, 26804566, 30968594). 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 I172N. ClinVar contains an entry for this variant (Variation ID: 12150). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of CAH (PMIDs: 3257825 (1988), 17042033 (2006), 21098686 (2011), 23359698 (2013), 31586465 (2020)). In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014)). The frequency of this variant in the general population, 0.0016 (41/25010 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This variant in exon 4 of the CYP21A2 gene results in the amino acid substitution from Isoleucine to Asparagine at codon 173 (p.Ile173Asn) with the sequence change of c.518T>A (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (86.9 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.000798722 and 0.0005771 in the 1000G database and gnomAD database respectively. The nucleotide is predicted conserved by GERP++ and PhyloP and the in-silico predictions by MutationTaster and SIFT are damaging. This variant lies in the p450 domain of CP21A_HUMAN protein (http://pfam.xfam.org/protein/P08686). This variant (also referred as Ile172Asn) has been previously reported for congenital adrenal hyperplasia (Amor et al., 1988;PMID: 3257825, Speiser et al., 1992;PMID: 1644925, New et al., 2013;PMID: 23359698). Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990;PMID: 2249999, Chiou et al., 1990;PMID: 2303461, Brønstad et al., 2014;PMID: 24671123).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 mutation update: Comprehensive analysis of databases and published genetic variants. | Simonetti L | Human mutation | 2018 | PMID: 29035424 |
| 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 |
| High frequency of splice site mutation in 21-hydroxylase deficiency children. | Sharaf S | Journal of endocrinological investigation | 2015 | PMID: 25501839 |
| Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia. | Brønstad I | Endocrine connections | 2014 | PMID: 24671123 |
| Functional studies of p.R132C, p.R149C, p.M283V, p.E431K, and a novel c.652-2A>G mutations of the CYP21A2 gene. | Taboas M | PloS one | 2014 | PMID: 24667412 |
| 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 |
| 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 |
| 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 |
| Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Falhammar H | European journal of endocrinology | 2011 | PMID: 21098686 |
| Classic virilizing congenital adrenal hyperplasia presenting late: case series from Pakistan. | Khan AH | JPMA. The Journal of the Pakistan Medical Association | 2009 | PMID: 19750867 |
| Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis. | Ezquieta B | Prenatal diagnosis | 2006 | PMID: 17042033 |
| An 88-year-old woman diagnosed with adrenal tumor and congenital adrenal hyperplasia: connection or coincidence? | Falhammar H | Journal of endocrinological investigation | 2005 | PMID: 16075929 |
| Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia. | Dolzan V | European journal of endocrinology | 2005 | PMID: 15994751 |
| Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein. | Félix-López X | Journal of pediatric endocrinology & metabolism : JPEM | 2003 | PMID: 14513879 |
| 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 |
| An intron 1 splice mutation and a nonsense mutation (W23X) in CYP21 causing severe congenital adrenal hyperplasia. | Lajic S | Human genetics | 1996 | PMID: 8698338 |
| Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. | Wedell A | The Journal of clinical endocrinology and metabolism | 1994 | PMID: 8175971 |
| A steroid 21-hydroxylase allele concomitantly carrying four disease-causing mutations is not uncommon in the swedish population. | Wedell A | Human genetics | 1994 | PMID: 8112748 |
| Mutations in steroid 21-hydroxylase (CYP21). | White PC | Human mutation | 1994 | PMID: 8081391 |
| Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | Speiser PW | The Journal of clinical investigation | 1992 | PMID: 1644925 |
| 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 |
| Substitution of Ile-172 to Asn in the steroid 21-hydroxylase B (P450c21B) gene in a Finnish patient with the simple virilizing form of congenital adrenal hyperplasia. | Partanen J | Human genetics | 1991 | PMID: 1937474 |
| A missense mutation at Ile172----Asn or Arg356----Trp causes steroid 21-hydroxylase deficiency. | Chiou SH | The Journal of biological chemistry | 1990 | PMID: 2303461 |
| 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 |
| Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency. | Amor M | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3257825 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2 | - | - | - | - |
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Text-mined citations for rs6475 ...
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Record last updated Sep 29, 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.