ClinVar Genomic variation as it relates to human health
NM_000781.3(CYP11A1):c.940G>A (p.Glu314Lys)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(4); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000781.3(CYP11A1):c.940G>A (p.Glu314Lys)
Variation ID: 372354 Accession: VCV000372354.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q24.1 15: 74343027 (GRCh38) [ NCBI UCSC ] 15: 74635368 (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 Jan 9, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000781.3:c.940G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000772.2:p.Glu314Lys missense NM_001099773.2:c.466G>A NP_001093243.1:p.Glu156Lys missense NC_000015.10:g.74343027C>T NC_000015.9:g.74635368C>T NG_007973.1:g.29715G>A - Protein change
- E314K, E156K
- Other names
- -
- Canonical SPDI
- NC_000015.10:74343026:C:T
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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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Trans-Omics for Precision Medicine (TOPMed) 0.00221
Exome Aggregation Consortium (ExAC) 0.00242
The Genome Aggregation Database (gnomAD), exomes 0.00253
The Genome Aggregation Database (gnomAD) 0.00262
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00285
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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CYP11A1 | - | - |
GRCh38 GRCh38 GRCh37 |
312 | 352 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000413593.9 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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May 19, 2023 | RCV000989359.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 7, 2023 | RCV001821140.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992284.1 |
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. |
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Likely pathogenic
(May 10, 2016)
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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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GeneDx
Accession: SCV000490512.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The E314K variant has been reported previously in two unrelated individuals with primary adrenal insufficiency; one individual harbored another CYP11A1 variant in trans whereas the … (more)
The E314K variant has been reported previously in two unrelated individuals with primary adrenal insufficiency; one individual harbored another CYP11A1 variant in trans whereas the other reported individual had no other molecular findings (Chan et al., 2015). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports E314K was observed in 0.34% (29/8,592) alleles from individuals of European American ancestry. The E314K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The E314K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139655.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001277696.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440455.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
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Pathogenic
(Jan 31, 2024)
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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: SCV001036285.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 314 of the CYP11A1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 314 of the CYP11A1 protein (p.Glu314Lys). This variant is present in population databases (rs6161, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary adrenal insufficiency (PMID: 30299480, 30620006). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has only been described in association with primary adrenal insufficiency, when present in trans with another loss of function allele. This variant is not associated with primary adrenal insufficiency when present in the homozygous state. ClinVar contains an entry for this variant (Variation ID: 372354). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752541.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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Likely benign
(Jul 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064629.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013235.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PM3
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Uncertain significance
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003830385.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844772.2
First in ClinVar: Mar 26, 2023 Last updated: Feb 04, 2024 |
Comment:
Variant summary: CYP11A1 c.940G>A (p.Glu314Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: CYP11A1 c.940G>A (p.Glu314Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.0025 in 251458 control chromosomes, including 4 homozygotes, and is found predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP11A1 causing Congenital Adrenal Hyperplasia phenotype (0.00091), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the inability of this data to distinguish the occurrence of this variant in a pseudogene versus the real CYP11A1 gene makes this data unreliable to formulate conclusive opinions. c.940G>A has been reported in the literature in the compound heterozygous state in individuals affected with Adrenal Insufficiency, including multiple cases where it has been reported in trans with a pathogenic variant and in families where it was reported to segregate with the disease phenotype (e.g. Chan_2015, Goursaud_2018, Maharaj_2019, Kolli_2019a), suggesting that the variant is very likely to be associated with disease. To our knowledge, the variant has not been reported in the homozygous state in affected individuals. Several publications report experimental evidence evaluating an impact on protein function (e.g. Goursaud_2018, Maharaj_2019, Kolli_2019a). Minigene assays have indicated that the variant affects mRNA splicing, resulting in the skipping of exon 5, which would result in a frameshift leading to a premature termination codon, and analysis of mRNA from an individual with the variant showed that this occurred in a larger proportion of transcripts than in a control individual, but that not all transcripts were affected. Enzyme activity assays have provided mixed results regarding the variant effect on protein function. Expression of the purified E314K variant protein in Ecoli and expression in COS1 cells showed comparable activity to the WT protein. However, it exhibited reduced protein expression/stability in HEK-293 cells, with approximately 60% activity compared to WT and in V9 cells, enzyme activity was undetectable. The following publications have been ascertained in the context of this evaluation (PMID: 26300845, 30233493, 30299480, 30620006). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1)/likely pathogenic (n=3), benign (n=1)/likely benign (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809548.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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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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Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency. | Kolli V | The Journal of clinical endocrinology and metabolism | 2019 | PMID: 30299480 |
Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing. | Maharaj A | Journal of the Endocrine Society | 2018 | PMID: 30620006 |
Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in CYP11A1 Gene. | Goursaud C | Frontiers in endocrinology | 2018 | PMID: 30233493 |
Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children. | Chan LF | Frontiers in endocrinology | 2015 | PMID: 26300845 |
Text-mined citations for rs6161 ...
HelpRecord last updated May 08, 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.