ClinVar Genomic variation as it relates to human health
NM_000044.6(AR):c.1174C>T (p.Pro392Ser)
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.
Uncertain significance(1); Benign(5); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000044.6(AR):c.1174C>T (p.Pro392Ser)
Variation ID: 216890 Accession: VCV000216890.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq12 X: 67546320 (GRCh38) [ NCBI UCSC ] X: 66766162 (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 Oct 11, 2015 Aug 4, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000044.6:c.1174C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000035.2:p.Pro392Ser missense NM_001011645.3:c.-610C>T 5 prime UTR NM_001348061.1:c.1174C>T NP_001334990.1:p.Pro392Ser missense NM_001348063.1:c.1174C>T NP_001334992.1:p.Pro392Ser missense NM_001348064.1:c.1174C>T NP_001334993.1:p.Pro392Ser missense NC_000023.11:g.67546320C>T NC_000023.10:g.66766162C>T NG_009014.2:g.7289C>T LRG_1406:g.7289C>T LRG_1406t1:c.1174C>T LRG_1406p1:p.Pro392Ser P10275:p.Pro392Ser - Protein change
- P392S
- Other names
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- Canonical SPDI
- NC_000023.11:67546319: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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0.00742 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00163
Trans-Omics for Precision Medicine (TOPMed) 0.00176
The Genome Aggregation Database (gnomAD), exomes 0.00448
1000 Genomes Project 0.00742
1000 Genomes Project 30x 0.00749
Exome Aggregation Consortium (ExAC) 0.00804
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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AR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
810 | 1021 |
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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Jan 25, 2024 | RCV000196772.10 | |
Benign (1) |
criteria provided, single submitter
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Sep 22, 2016 | RCV000499525.13 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 31, 2018 | RCV000627669.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000990850.14 | |
Benign (6) |
criteria provided, single submitter
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Jul 1, 2024 | RCV001269900.24 | |
Benign (1) |
criteria provided, single submitter
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Feb 21, 2022 | RCV002221510.9 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001516905.14 | |
AR-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Jul 2, 2023 | RCV003927863.1 |
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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Benign
(Sep 22, 2016)
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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: SCV000593280.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Benign
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Androgen resistance syndrome
Partial androgen insensitivity syndrome (X-linked recessive inheritance)
Affected status: no
Allele origin:
germline
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Pars Genome Lab
Accession: SCV002098054.1
First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
Sex: mixed
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Benign
(Jan 31, 2024)
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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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Invitae
Accession: SCV001725277.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024 |
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Benign
(Feb 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Androgen resistance syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141898.2
First in ClinVar: Jan 09, 2020 Last updated: Mar 05, 2024 |
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Likely benign
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Androgen resistance syndrome
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV004190290.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
ACMG:PM1 PP3 BS1 BP2 BP4
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Likely benign
(Jul 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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AR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004738456.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Androgen resistance syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809909.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Benign
(Jul 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: SCV004165241.8
First in ClinVar: Nov 20, 2023 Last updated: Aug 04, 2024 |
Comment:
AR: PP3, BS1, BS2
Number of individuals with the variant: 16
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Uncertain significance
(Jan 31, 2018)
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no assertion criteria provided
Method: clinical testing
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Hypospadias 1, X-linked
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000746022.1
First in ClinVar: May 21, 2018 Last updated: May 21, 2018 |
Comment:
The observed variant c.1174C>T (p.P392S) has the minor allele frequency of 0.74% in 1000 Genomes and 0.8% in ExAC databases. The in silico predictions of … (more)
The observed variant c.1174C>T (p.P392S) has the minor allele frequency of 0.74% in 1000 Genomes and 0.8% in ExAC databases. The in silico predictions of the variant is polymorphism by Mutation Taster, benign by PolyPhen and damaging by SIFT. (less)
Clinical Features:
Hypospadias (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Gujarati Hindu
Geographic origin: India
Method: The DNA isolated from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina Sequencing platform. The sequencing obtained were aligned to the human reference genome (GRCh37/hg19) using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted gene relevant to clinical indication.
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549096.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The AR p.Pro392Ser variant was identified in 4 of 584 proband chromosomes (frequency: 0.00685) from a Caucasian population presenting with isolated hypospadias without micropenis or … (more)
The AR p.Pro392Ser variant was identified in 4 of 584 proband chromosomes (frequency: 0.00685) from a Caucasian population presenting with isolated hypospadias without micropenis or cryptorchidism, and was not identified in 690 control chromosomes from healthy individuals (Kalfa_2013_23637914). The variant was also identified in dbSNP (ID: rs201934623) as "With Pathogenic allele" and ClinVar (3 submissions with conflicting interpretations of pathogenicity: Benign(1) by Genetic Services Laboratory, University of Chicago (2016); Pathogenic(1) by UCLA Clinical Genomics Center, UCLA - CES (2014); and Uncertain significance(1) by Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics (2018)). Submitters report the variant to be linked to Partial Androgen Insensitivity syndrome and Hypospadias 1, X-linked. The variant was also identified in Clinvitae, Cosmic, MutDB, and LOVD 3.0 (likely benign). The variant was identified in control databases in 684 of 166808 chromosomes (4 homozygous) at a frequency of 0.004101 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 404 of 16297 chromosomes (freq: 0.02479), Other in 16 of 4579 chromosomes (freq: 0.003494), Ashkenazi Jewish in 22 of 6922 chromosomes (freq: 0.003178), European (non-Finnish) in 189 of 71137 chromosomes (freq: 0.002657), Latino in 46 of 25450 chromosomes (freq: 0.001807), African in 5 of 14750 chromosomes (freq: 0.000339), East Asian in 1 of 12487 chromosomes (freq: 0.00008), and European (Finnish) in 1 of 15186 chromosomes (freq: 0.000066). Chakrabarty et al. identified the variant p.Pro392Ser as a somatic driver mutation in tissue samples of 18 long-standing ulcerative colitis (UC) subjects at high risk of colorectal carcinoma. (Chakrabarty_2017_28524162). The p.Pro392Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Chakrabarty, Sanjiban, et al. "Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia." British journal of cancer 117.1 (2017): 136. Kalfa, Nicolas, et al. "Minor hypospadias: the “tip of the iceberg” of the partial androgen insensitivity syndrome." PloS one 8.4 (2013): e61824. (less)
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Likely benign
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799543.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972056.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely benign
(-)
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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: SCV001978058.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Jul 01, 2014)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Reifenstein syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
unknown
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255325.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 20-29 years
Sex: female
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(Aug 20, 2014)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450250.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development. | Phelan N | European journal of endocrinology | 2015 | PMID: 25740850 |
Text-mined citations for rs201934623 ...
HelpRecord last updated Aug 25, 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.