ClinVar Genomic variation as it relates to human health
NM_000498.3(CYP11B2):c.554C>T (p.Thr185Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000498.3(CYP11B2):c.554C>T (p.Thr185Ile)
Variation ID: 16881 Accession: VCV000016881.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.3 8: 142915087 (GRCh38) [ NCBI UCSC ] 8: 143996503 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000498.3:c.554C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000489.3:p.Thr185Ile missense NC_000008.11:g.142915087G>A NC_000008.10:g.143996503G>A NG_008374.1:g.7757C>T NG_046133.1:g.11730G>A P19099:p.Thr185Ile - Protein change
- T185I
- Other names
- -
- Canonical SPDI
- NC_000008.11:142915086:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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
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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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CYP11B2 | - | - |
GRCh38 GRCh37 |
19 | 722 | |
LOC106799834 | - | - | - | GRCh38 | - | 660 |
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2023 | RCV000018377.30 | |
Pathogenic (1) |
criteria provided, single submitter
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May 24, 2022 | RCV002496398.2 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000808165.24 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 28, 2020 | RCV001826477.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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. |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447926.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Global developmental delay (present) , Marked delay in bone age (present) , Short stature (present)
Sex: male
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Corticosterone methyloxidase type 2 deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572992.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Functional studies provide strong evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12788848 , 21237269). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 12788848 , 22565077 , 22931312 , 9625333). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal facial shape (present) , Wide nasal ridge (present) , Depressed nasal bridge (present) , Low-set ears (present) , Small forehead (present) , Slender finger … (more)
Abnormal facial shape (present) , Wide nasal ridge (present) , Depressed nasal bridge (present) , Low-set ears (present) , Small forehead (present) , Slender finger (present) , Long foot (present) , Joint laxity (present) , Hyponatremia (present) , Hyperkalemia (present) , Dehydration (present) (less)
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Pathogenic
(May 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Corticosterone 18-monooxygenase deficiency
Corticosterone methyloxidase type 2 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809736.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Corticosterone methyloxidase type 2 deficiency
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV004190318.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
ACMG:PS3 PM2 PM3 PP4
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000948259.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 185 of the CYP11B2 protein (p.Thr185Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 185 of the CYP11B2 protein (p.Thr185Ile). This variant is present in population databases (rs121912978, gnomAD 0.009%). This missense change has been observed in individuals with hypoaldosteronism (PMID: 9625333, 12788848, 22565077, 22931312). ClinVar contains an entry for this variant (Variation ID: 16881). 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 CYP11B2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CYP11B2 function (PMID: 12788848, 21237269). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962157.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Comment:
CYP11B2: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(Jun 01, 2003)
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no assertion criteria provided
Method: literature only
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CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038659.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with CMO type II deficiency, Peter et al. (1998) demonstrated homozygosity for a C-to-T transition in the CYP11B2 gene, resulting in a … (more)
In a patient with CMO type II deficiency, Peter et al. (1998) demonstrated homozygosity for a C-to-T transition in the CYP11B2 gene, resulting in a thr185-to-ile (T185I) substitution. Both parents were heterozygous carriers for the mutation. The elevated ratio of 18-hydroxycorticosterone to aldosterone in the plasma was considered pathognomonic for CMO deficiency type II. The patient, born of consanguineous Hungarian gypsies, had originally been reported by Hauffa et al. (1991). Dunlop et al. (2003) reported this mutation, which arises from a 554C-T transition, in an infant with CMO type II deficiency. This patient was compound heterozygous for T185I and a T498A substitution (124080.0012). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928369.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001959493.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Mar 28, 2020)
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no assertion criteria provided
Method: clinical testing
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Corticosterone methyl oxidase type II deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083102.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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Homozygosity for a mutation in the CYP11B2 gene in an infant with congenital corticosterone methyl oxidase deficiency type II. | Jessen CL | Acta paediatrica (Oslo, Norway : 1992) | 2012 | PMID: 22931312 |
Aldosterone synthase deficiency type II with hypospadias. | Gucev Z | Indian pediatrics | 2012 | PMID: 22565077 |
Fission yeast Schizosaccharomyces pombe as a new system for the investigation of corticosterone methyloxidase deficiency-causing mutations. | Tin MK | The Journal of steroid biochemistry and molecular biology | 2011 | PMID: 21237269 |
A compound heterozygote case of type II aldosterone synthase deficiency. | Dunlop FM | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12788848 |
Mutation THR-185 ILE is associated with corticosterone methyl oxidase deficiency type II. | Peter M | European journal of pediatrics | 1998 | PMID: 9625333 |
Severe hypoaldosteronism due to corticosterone methyl oxidase type II deficiency in two boys: metabolic and gas chromatography-mass spectrometry studies. | Hauffa BP | European journal of pediatrics | 1991 | PMID: 2044581 |
Text-mined citations for rs121912978 ...
HelpRecord last updated Apr 15, 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.