VCV000009813.10 - ClinVar

NM_000044.6(AR):c.1789G>A (p.Ala597Thr)

Germline

Classification

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000044.6(AR):c.1789G>A (p.Ala597Thr)

Variation ID: 9813 Accession: VCV000009813.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq12 X: 67686030 (GRCh38) [ NCBI UCSC ] X: 66905872 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 24, 2024	Oct 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000044.6:c.1789G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000035.2:p.Ala597Thr	missense
NM_001011645.3:c.193G>A	NP_001011645.1:p.Ala65Thr	missense
NM_001348061.1:c.1789G>A	NP_001334990.1:p.Ala597Thr	missense
NM_001348063.1:c.1789G>A	NP_001334992.1:p.Ala597Thr	missense
NM_001348064.1:c.1706G>A	NP_001334993.1:p.Arg569His	missense
NC_000023.11:g.67686030G>A
NC_000023.10:g.66905872G>A
NG_009014.2:g.146999G>A
LRG_1406:g.146999G>A
LRG_1406t1:c.1789G>A	LRG_1406p1:p.Ala597Thr
	P10275:p.Ala597Thr

... more HGVS ... less HGVS

Protein change

A597T, A65T, R569H

Other names

A771T

Canonical SPDI

NC_000023.11:67686029:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA120703 UniProtKB: P10275#VAR_009743 OMIM: 313700.0011 dbSNP: rs137852569 VarSome

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
Gene	OMIM	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.
AR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	821	1035

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.
Partial androgen insensitivity syndrome	Pathogenic (3)	criteria provided, single submitter	Oct 8, 2024	RCV000010487.4
Androgen resistance syndrome Kennedy disease	Pathogenic (1)	criteria provided, single submitter	Dec 17, 2023	RCV000640478.7
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 15, 2018	RCV001269612.2

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.
Pathogenic (Mar 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449713.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 2
Pathogenic (Dec 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000762070.4 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 1598912‚ 26778393‚ 28261839 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 597 of the AR protein (p.Ala597Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 597 of the AR protein (p.Ala597Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with AR-related conditions (PMID: 1598912, 26778393, 28261839). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9813). 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. Experimental studies have shown that this missense change affects AR function (PMID: 1598912). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Partial androgen insensitivity syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398349.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 1598912‚ 10971094‚ 15963062‚ 26778393‚ 28261839‚ 29051026‚ 29785970 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with androgen insensitivity (MIM#300068), partial androgen insensitivity with or without breast cancer (MIM#312300), X-linked hypospadias 1 (MIM#300633), or spinal and bulbar muscular atrophy of Kennedy (MIM#313200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Zinc finger, C4 type DNA binding domain (DECIPHER, PMID: 29051026). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in more than ten individuals with partial androgen insensitivity syndrome (PAIS) (ClinVar, PMIDs: 10971094, 15963062, 1598912, 26778393, 28261839, 29785970, 29051026). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 01, 1992)	no assertion criteria provided Method: literature only	ANDROGEN INSENSITIVITY, PARTIAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030713.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 1598912 Comment on evidence: In 2 unrelated families, Klocker et al. (1992) demonstrated that the Reifenstein syndrome (312300) was due to a G-to-A transition at nucleotide 2314 of the … (more) In 2 unrelated families, Klocker et al. (1992) demonstrated that the Reifenstein syndrome (312300) was due to a G-to-A transition at nucleotide 2314 of the AR gene, which changed the alanine codon (GCC) immediately after the first cysteine of the second zinc finger motif of the androgen receptor into a threonine codon (ACC). The 5 patients in the 2 families presented with perineoscrotal hypospadias and undescended testes. After puberty they showed small testes, no palpable prostate, micropenis, azoospermia, and gynecomastia. (less)
Pathogenic (Nov 04, 2022)	no assertion criteria provided Method: clinical testing	Partial androgen insensitivity syndrome Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV004808327.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 597 of the AR protein (p.Ala597Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with AR-related conditions (PMID: 1598912, 26778393, 28261839). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9813). 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. Experimental studies have shown that this missense change affects AR function (PMID: 1598912). For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with androgen insensitivity (MIM#300068), partial androgen insensitivity with or without breast cancer (MIM#312300), X-linked hypospadias 1 (MIM#300633), or spinal and bulbar muscular atrophy of Kennedy (MIM#313200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Zinc finger, C4 type DNA binding domain (DECIPHER, PMID: 29051026). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in more than ten individuals with partial androgen insensitivity syndrome (PAIS) (ClinVar, PMIDs: 10971094, 15963062, 1598912, 26778393, 28261839, 29785970, 29051026). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.	Yuan SM	Asian journal of andrology	2018	PMID: 29785970
Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD.	Ramos L	Gene	2018	PMID: 29051026
Clinical and molecular characteristics in 15 patients with androgen receptor gene mutations from South China.	Su L	Andrologia	2017	PMID: 28261839
Androgen insensitivity syndrome in a cohort of Sri Lankan children with 46, XY disorders of sex development (46, XY DSD).	de Silva KS	The Ceylon medical journal	2015	PMID: 26778393
Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome.	Deeb A	Clinical endocrinology	2005	PMID: 15963062
Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor.	Lundberg Giwercman Y	Hormone research	2000	PMID: 10971094
Point mutation in the DNA binding domain of the androgen receptor in two families with Reifenstein syndrome.	Klocker H	American journal of human genetics	1992	PMID: 1598912

Text-mined citations for rs137852569 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000044.6(AR):c.1789G>A (p.Ala597Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852569 ...