This sequence change creates a premature translational stop signal (p.Tyr423*) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs267606755, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with non-classic 11-beta-hydroxylase deficiency (PMID: 9302260). ClinVar contains an entry for this variant (Variation ID: 1185). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000497.4(CYP11B1):c.1269T>G (p.Tyr423Ter)
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.
(7)
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000497.4(CYP11B1):c.1269T>G (p.Tyr423Ter)
Variation ID: 1185 Accession: VCV000001185.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.3 8: 142875086 (GRCh38) [ NCBI UCSC ] 8: 143956502 (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 Jun 17, 2024 Mar 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000497.4:c.1269T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000488.3:p.Tyr423Ter nonsense NM_001026213.1:c.1200+148T>G intron variant NC_000008.11:g.142875086A>C NC_000008.10:g.143956502A>C NG_007954.1:g.9735T>G NG_046132.1:g.953A>C - Protein change
- Y423*
- Other names
- -
- Canonical SPDI
- NC_000008.11:142875085:A:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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. |
|||
| CYP11B1 | - | - |
GRCh38 GRCh37 |
210 | 901 | |
| LOC106799833 | - | - | - | GRCh38 | - | 616 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2024 | RCV000001244.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 17, 2024 | RCV001851530.6 | |
|
CYP11B1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 18, 2022 | RCV003415613.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of steroid 11-beta-monooxygenase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790308.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002226157.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr423*) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr423*) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs267606755, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with non-classic 11-beta-hydroxylase deficiency (PMID: 9302260). ClinVar contains an entry for this variant (Variation ID: 1185). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of steroid 11-beta-monooxygenase
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967661.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Tyr423X variant in CYP11B1 has been reported in the compound heterozygote state in 1 individual with non-classic adrenal hyperplasia due to 11 beta-hydrox ylase … (more)
The p.Tyr423X variant in CYP11B1 has been reported in the compound heterozygote state in 1 individual with non-classic adrenal hyperplasia due to 11 beta-hydrox ylase deficiency (Joehrer 1997). This variant has been identified in 2/126704 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs267606755). This nonsense variant leads to a premature termination codon at position 423 which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets criteria to be classified as patho genic for non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency in an autosomal recessive manner based upon a case report, low frequency in con trols and predicted impact on protein. Criteria applied: PVS1, PM2, PM3_Supporti ng. (less)
Number of individuals with the variant: 1
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of steroid 11-beta-monooxygenase
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573252.1
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: <0.001%). Stop-gained (nonsense) is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001185 / PMID: 9302260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Ambiguous genitalia (present) , Clitoral hypertrophy (present) , Precocious puberty in females (present)
|
|
|
Pathogenic
(Nov 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
CYP11B1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116976.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CYP11B1 c.1269T>G variant is predicted to result in premature protein termination (p.Tyr423*). This variant was reported in an individual with steroid-11 beta-hydroxylase deficiency (Joehrer … (more)
The CYP11B1 c.1269T>G variant is predicted to result in premature protein termination (p.Tyr423*). This variant was reported in an individual with steroid-11 beta-hydroxylase deficiency (Joehrer et al. 1997. PubMed ID: 9302260). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143956502-A-C). Nonsense variants in CYP11B1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of steroid 11-beta-monooxygenase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215337.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Oct 01, 1997)
|
no assertion criteria provided
Method: literature only
|
ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021394.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 26, 2022 |
Comment on evidence:
In a patient with partial steroid 11-beta-hydroxylase deficiency (202010), Joehrer et al. (1997) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: tyr423-to-ter (Y423X) … (more)
In a patient with partial steroid 11-beta-hydroxylase deficiency (202010), Joehrer et al. (1997) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: tyr423-to-ter (Y423X) and P42S (610613.0009). (less)
|
Comment:
Comment:
The p.Tyr423X variant in CYP11B1 has been reported in the compound heterozygote state in 1 individual with non-classic adrenal hyperplasia due to 11 beta-hydrox ylase deficiency (Joehrer 1997). This variant has been identified in 2/126704 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs267606755). This nonsense variant leads to a premature termination codon at position 423 which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets criteria to be classified as patho genic for non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency in an autosomal recessive manner based upon a case report, low frequency in con trols and predicted impact on protein. Criteria applied: PVS1, PM2, PM3_Supporti ng.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001185 / PMID: 9302260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The CYP11B1 c.1269T>G variant is predicted to result in premature protein termination (p.Tyr423*). This variant was reported in an individual with steroid-11 beta-hydroxylase deficiency (Joehrer et al. 1997. PubMed ID: 9302260). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143956502-A-C). Nonsense variants in CYP11B1 are expected to be pathogenic. This variant is interpreted as pathogenic.
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:
This sequence change creates a premature translational stop signal (p.Tyr423*) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs267606755, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with non-classic 11-beta-hydroxylase deficiency (PMID: 9302260). ClinVar contains an entry for this variant (Variation ID: 1185). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Tyr423X variant in CYP11B1 has been reported in the compound heterozygote state in 1 individual with non-classic adrenal hyperplasia due to 11 beta-hydrox ylase deficiency (Joehrer 1997). This variant has been identified in 2/126704 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs267606755). This nonsense variant leads to a premature termination codon at position 423 which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets criteria to be classified as patho genic for non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency in an autosomal recessive manner based upon a case report, low frequency in con trols and predicted impact on protein. Criteria applied: PVS1, PM2, PM3_Supporti ng.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001185 / PMID: 9302260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The CYP11B1 c.1269T>G variant is predicted to result in premature protein termination (p.Tyr423*). This variant was reported in an individual with steroid-11 beta-hydroxylase deficiency (Joehrer et al. 1997. PubMed ID: 9302260). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143956502-A-C). Nonsense variants in CYP11B1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene. | Nguyen HH | The Journal of steroid biochemistry and molecular biology | 2016 | PMID: 26476331 |
| CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. | Joehrer K | Human molecular genetics | 1997 | PMID: 9302260 |
| Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. | Curnow KM | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8506298 |
Text-mined citations for rs267606755 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
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.