ClinVar Genomic variation as it relates to human health
NM_000054.7(AVPR2):c.541C>T (p.Arg181Cys)
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_000054.7(AVPR2):c.541C>T (p.Arg181Cys)
Variation ID: 10850 Accession: VCV000010850.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 153906047 (GRCh38) [ NCBI UCSC ] X: 153171501 (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 Jul 25, 2015 Jul 23, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000054.7:c.541C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000045.1:p.Arg181Cys missense NM_001146151.3:c.541C>T NP_001139623.1:p.Arg181Cys missense NR_027419.2:n.494C>T non-coding transcript variant NC_000023.11:g.153906047C>T NC_000023.10:g.153171501C>T NG_008687.1:g.6074C>T NG_013220.1:g.25214G>A LRG_716:g.6074C>T LRG_716t1:c.541C>T LRG_716p1:p.Arg181Cys P30518:p.Arg181Cys - Protein change
- R181C
- Other names
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- Canonical SPDI
- NC_000023.11:153906046: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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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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AVPR2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
304 | 565 |
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 (2) |
criteria provided, single submitter
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Apr 9, 2020 | RCV000011597.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2023 | RCV002472927.2 |
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
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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
(Nov 28, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563731.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The AVPR2 c.541C>T; p.Arg181Cys variant (rs104894757) is reported in the literature in several individuals affected with X-linked nephrogenic diabetes insipidus (Pan 1992, Sahakitrungruang 2010, Schoneberg … (more)
The AVPR2 c.541C>T; p.Arg181Cys variant (rs104894757) is reported in the literature in several individuals affected with X-linked nephrogenic diabetes insipidus (Pan 1992, Sahakitrungruang 2010, Schoneberg 1998, Shelihan 2021). This variant is also reported in ClinVar (Variation ID: 10850). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism, but is considered a low confidence variant in the database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.639). Functional studies demonstrate that this variant leads to abnormal protein function (Armstrong 2013, Sahakitrungruang 2010, Schoneberg 1998). Based on available information, this variant is considered to be pathogenic. References: Armstrong SP et al. Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V). PLoS One. 2013 Jun 6;8(6):e65885. PMID: 23762448. Pan Y et al. Mutations in the V2 vasopressin receptor gene are associated with X-linked nephrogenic diabetes insipidus. Nat Genet. 1992 Oct;2(2):103-6. PMID: 1303257. Sahakitrungruang T et al. Functional characterization of vasopressin receptor 2 mutations causing partial and complete congenital nephrogenic diabetes insipidus in Thai families. Horm Res Paediatr. 2010;73(5):349-54. PMID: 20389105. Schoneberg T et al. V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms. Hum Mutat. 1998;12(3):196-205. PMID: 9711877. Shelihan I et al. Infantile onset carnitine palmitoyltransferase 2 deficiency: Cortical polymicrogyria, schizencephaly, and gray matter heterotopias in an adolescent with normal development. JIMD Rep. 2021 Sep 29;63(1):3-10. PMID: 35028265. (less)
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Pathogenic
(Apr 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Diabetes insipidus, nephrogenic, X-linked
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557896.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a cysteine (exon 3). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (48 heterozygotes, 0 homozygotes, 12 hemizygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (extracellular region of the 7tm vasopressin receptor 2 super family; NCBI, PDB, Decipher) (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Spanakis, E., et al. (2008), Bichet, D., et al. (1994)) (P) 1001 - Strong functional evidence supporting abnormal protein function (Tiulpakov, A., et al. (2016), Armstrong, S., et al. (2013)) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Jun 27, 2022)
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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: SCV002770348.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20389105, 10644689, 1303257, 34839503, 23762448, 27355191, 9711877, 34101133, 16825342, 33392325, 8766931, 8037205, 18726898, 24030030, 1357965, 35028265) (less)
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Pathogenic
(Jan 01, 1998)
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no assertion criteria provided
Method: literature only
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DIABETES INSIPIDUS, NEPHROGENIC, 1, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031829.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 26, 2021 |
Comment on evidence:
In affected members of a German family with nephrogenic diabetes insipidus (NDI1; 304800), Schoneberg et al. (1998) identified a C-to-T transition in the AVPR2 gene, … (more)
In affected members of a German family with nephrogenic diabetes insipidus (NDI1; 304800), Schoneberg et al. (1998) identified a C-to-T transition in the AVPR2 gene, resulting in an arg181-to-cys (R181C) substitution. Functional expression studies showed that the R181C mutant protein is properly delivered to the cell surface, but shows impaired ligand binding. This mutation had previously been identified in an American kindred, where it was found in combination with an additional deletion of 4 amino acids in the third intracellular loop (Pan et al., 1992). (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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Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking. | Tiulpakov A | Molecular endocrinology (Baltimore, Md.) | 2016 | PMID: 27355191 |
Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V). | Armstrong SP | PloS one | 2013 | PMID: 23762448 |
AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. | Spanakis E | Journal of cellular physiology | 2008 | PMID: 18726898 |
V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms. | Schöneberg T | Human mutation | 1998 | PMID: 9711877 |
Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. | Bichet DG | American journal of human genetics | 1994 | PMID: 8037205 |
Mutations in the V2 vasopressin receptor gene are associated with X-linked nephrogenic diabetes insipidus. | Pan Y | Nature genetics | 1992 | PMID: 1303257 |
Text-mined citations for rs104894757 ...
HelpRecord last updated Jul 23, 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.