ClinVar Genomic variation as it relates to human health
NM_000044.6(AR):c.2522G>A (p.Arg841His)
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_000044.6(AR):c.2522G>A (p.Arg841His)
Variation ID: 9829 Accession: VCV000009829.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq12 X: 67722899 (GRCh38) [ NCBI UCSC ] X: 66942741 (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 Feb 19, 2018 Feb 28, 2024 Jul 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000044.6:c.2522G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000035.2:p.Arg841His missense NM_001011645.3:c.926G>A NP_001011645.1:p.Arg309His missense NC_000023.11:g.67722899G>A NC_000023.10:g.66942741G>A NG_009014.2:g.183868G>A LRG_1406:g.183868G>A LRG_1406t1:c.2522G>A LRG_1406p1:p.Arg841His P10275:p.Arg841His - Protein change
- R309H, R841H
- Other names
- R839H
- Canonical SPDI
- NC_000023.11:67722898: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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AR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
813 | 1024 |
Conditions - Germline
Condition
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (1) |
no assertion criteria provided
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Aug 1, 1994 | RCV000010503.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 10, 2019 | RCV001269861.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 4, 2023 | RCV000814875.7 | |
Pathogenic (2) |
criteria provided, single submitter
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- | RCV000582333.2 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Sep 10, 2019)
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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: SCV001768156.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Observed in several unrelated patients with androgen insensitivity syndrome in published literature (McPhaul et al., 1992; Beitel et al., 1994); Published functional studies demonstrate a … (more)
Observed in several unrelated patients with androgen insensitivity syndrome in published literature (McPhaul et al., 1992; Beitel et al., 1994); Published functional studies demonstrate a damaging effect on GH gene promotion as well as ligand binding (Beitel et al., 1994); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32985417, 3605226, 8040309, 28624954, 1430233, 28186600, 25241384, 16450583, 15835798, 27267075) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Androgen resistance syndrome
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013543.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009829 / PMID: 1430233). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 1430233, 16450583, 25241384, 28624954, 32985417). Different missense changes at the same codon (p.Arg841Cys, p.Arg841Gly, p.Arg841Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009830 / PMID: 10502786, 1430233, 9856504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Ambiguous genitalia (present) , Gonadal dysgenesis (present)
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Pathogenic
(Jul 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Kennedy disease
Androgen resistance syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000955308.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change affects AR function (PMID: 1430233, 8040309). For these reasons, this variant has been classified as Pathogenic. This … (more)
Experimental studies have shown that this missense change affects AR function (PMID: 1430233, 8040309). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg941 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430233, 8040309, 8824883, 11788673, 15925895, 20011049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. ClinVar contains an entry for this variant (Variation ID: 9829). This variant is also known as p.R838H, p.R839H, and p.R840H. This missense change has been observed in individuals with androgen insensitivity syndome (PMID: 1430233, 8040309, 16450583, 25241384, 27267075, 28186600, 28624954). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 841 of the AR protein (p.Arg841His). (less)
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Pathogenic
(Jan 21, 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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450175.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 30, 2007)
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no assertion criteria provided
Method: clinical testing
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Androgen resistance syndrome
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692167.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(Aug 01, 1994)
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no assertion criteria provided
Method: literature only
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ANDROGEN INSENSITIVITY, PARTIAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030729.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Beitel et al. (1994) described an arg839-to-his mutation in affected members of 2 families in whom external genitalia were predominantly female at birth and sex-of-rearing … (more)
Beitel et al. (1994) described an arg839-to-his mutation in affected members of 2 families in whom external genitalia were predominantly female at birth and sex-of-rearing had been female. In a third family, the external genitalia of affected members were predominantly male at birth, and sex-of-rearing had been male; however, these individuals carried an arg839-to-cys mutation (313700.0026). In genital skin fibroblasts, both mutant receptors had a normal androgen-binding capacity, but they differed in selected indices of affinity for dihydrotestosterone or 2 synthetic androgens. In transiently cotransfected androgen-treated COS-1 cells, both mutant receptors transactivated a reporter gene subnormally. The his839 mutant was less active than its partner, primarily because its androgen-binding activity was more unstable during prolonged exposure to androgen (see 312300). (less)
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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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Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing. | Yu BQ | Asian journal of andrology | 2021 | PMID: 32985417 |
AR mutations in 28 patients with androgen insensitivity syndrome (Prader grade 0-3). | Wang Y | Science China. Life sciences | 2017 | PMID: 28624954 |
[Analysis of AR gene mutation in a family affected with complete androgen insensitivity syndrome using long chain RT-PCR]. | Zhang X | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2017 | PMID: 28186600 |
Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer. | Disciglio V | Chinese journal of cancer | 2016 | PMID: 27267075 |
Mutation analysis of androgen receptor gene: multiple uses for a single test. | Shojaei A | Gene | 2014 | PMID: 25241384 |
Androgen receptor mutations associated with androgen insensitivity syndrome: a high content analysis approach leading to personalized medicine. | Szafran AT | PloS one | 2009 | PMID: 20011049 |
Genetic analysis of a family with 46,XY "female" associated with infertility. | Wang X | Yi chuan xue bao = Acta genetica Sinica | 2006 | PMID: 16450583 |
Novel and recurrent mutations in patients with androgen insensitivity syndromes. | Ledig S | Hormone research | 2005 | PMID: 15925895 |
Male fertility is compatible with an Arg(840)Cys substitution in the AR in a large Chinese family affected with divergent phenotypes of AR insensitivity syndrome. | Chu J | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 11788673 |
A novel point mutation (R840S) in the androgen receptor in a Brazilian family with partial androgen insensitivity syndrome. | Melo KF | Human mutation | 1999 | PMID: 10502786 |
Functional characterisation of mutations in the ligand-binding domain of the androgen receptor gene in patients with androgen insensitivity syndrome. | Lundberg Giwercman Y | Human genetics | 1998 | PMID: 9856504 |
Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. | Bevan CL | Human molecular genetics | 1996 | PMID: 8824883 |
Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance. | Beitel LK | The Journal of clinical investigation | 1994 | PMID: 8040309 |
Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene. | McPhaul MJ | The Journal of clinical investigation | 1992 | PMID: 1430233 |
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Text-mined citations for rs9332969 ...
HelpRecord 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.