Converted during submission to Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000486.6(AQP2):c.559C>T (p.Arg187Cys)
Germline
Classification
Help
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.
(7)
Help
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000486.6(AQP2):c.559C>T (p.Arg187Cys)
Variation ID: 17828 Accession: VCV000017828.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.12 12: 49954663 (GRCh38) [ NCBI UCSC ] 12: 50348446 (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 Apr 4, 2013 Feb 14, 2024 Jan 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000486.6:c.559C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000477.1:p.Arg187Cys missense NC_000012.12:g.49954663C>T NC_000012.11:g.50348446C>T NG_008913.1:g.8923C>T LRG_717:g.8923C>T LRG_717t1:c.559C>T LRG_717p1:p.Arg187Cys P41181:p.Arg187Cys - Protein change
- R187C
- Other names
- -
- Canonical SPDI
- NC_000012.12:49954662: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| AQP2 | - | - |
GRCh38 GRCh37 |
130 | 397 | |
| AQP5-AS1 | - | - | - | GRCh38 | - | 279 |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000019406.31 | |
| Pathogenic (2) |
criteria provided, single submitter
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Aug 18, 2011 | RCV000029344.3 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000808569.7 |
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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pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
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Nephrogenic Diabetes Insipidus
(autosomal recessive)
Affected status: yes, unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000051990.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Tissue: Blood
Observation 5:
Tissue: Blood
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Pathogenic
(Jul 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Diabetes insipidus, nephrogenic, autosomal
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810864.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Nov 17, 2021)
|
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: SCV002028190.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect due to protein misfolding and ER retention (Tamarappoo et al., 1998; Leduc-Nadeau et al., 2010); In silico analysis … (more)
Published functional studies demonstrate a damaging effect due to protein misfolding and ER retention (Tamarappoo et al., 1998; Leduc-Nadeau et al., 2010); 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: 10564236, 10228154, 20403973, 11374071, 11076974, 14593099, 10997928, 7537761, 7524315, 15509592, 8140421, 9593782) (less)
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Diabetes insipidus, nephrogenic, autosomal
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841728.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). The variant is located in a mutational … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017828). Different missense changes at the same codon (p.Arg187Gly, p.Arg187His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035695, VCV001481897). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Diabetes insipidus (present) , Anemia (present) , Thrombocytopenia (present) , Alopecia of scalp (present) , Hypernatremia (present)
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Pathogenic
(Jan 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000948681.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 187 of the AQP2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 187 of the AQP2 protein (p.Arg187Cys). This variant is present in population databases (rs104894328, gnomAD 0.008%). This missense change has been observed in individuals with nephrogenic diabetes insipidus (NDI) in a family and also has been observed as homozygous or in combination with another AQP2 variant in individuals affected with NDI (PMID: 7524315, 20403973). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17828). 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) performed at Invitae indicates that this missense variant is expected to disrupt AQP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AQP2 function (PMID: 9593782, 10228154, 10564236, 11374071, 20403973). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Nephrogenic diabetes insipidus
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458718.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Oct 01, 1994)
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no assertion criteria provided
Method: literature only
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DIABETES INSIPIDUS, NEPHROGENIC, 2, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039696.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 07, 2021 |
Comment on evidence:
In a male patient with nephrogenic diabetes insipidus (NDI2; 125800), Deen et al. (1994) identified compound heterozygosity for 2 mutations in the AQP2 gene: a … (more)
In a male patient with nephrogenic diabetes insipidus (NDI2; 125800), Deen et al. (1994) identified compound heterozygosity for 2 mutations in the AQP2 gene: a 559C-T transition in exon 3, resulting in an arg187-to-cys (R187C) substitution, and a 646T-C transition in exon 4, resulting in a ser216-to-pro (S216P; 107777.0002) substitution. The former mutation was inherited from the father and the latter from the mother. Functional expression studies in Xenopus oocytes showed that both mutations resulted in a nonfunctional protein. Van Lieburg et al. (1994) identified homozygosity for the R187C mutation in a Dutch patient with NDI. He was born of consanguineous parents; 3 other children in the family had died of severe dehydration and hypernatremia. (less)
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect due to protein misfolding and ER retention (Tamarappoo et al., 1998; Leduc-Nadeau et al., 2010); 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: 10564236, 10228154, 20403973, 11374071, 11076974, 14593099, 10997928, 7537761, 7524315, 15509592, 8140421, 9593782)
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017828). Different missense changes at the same codon (p.Arg187Gly, p.Arg187His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035695, VCV001481897). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 187 of the AQP2 protein (p.Arg187Cys). This variant is present in population databases (rs104894328, gnomAD 0.008%). This missense change has been observed in individuals with nephrogenic diabetes insipidus (NDI) in a family and also has been observed as homozygous or in combination with another AQP2 variant in individuals affected with NDI (PMID: 7524315, 20403973). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17828). 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) performed at Invitae indicates that this missense variant is expected to disrupt AQP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AQP2 function (PMID: 9593782, 10228154, 10564236, 11374071, 20403973). For these reasons, this variant has been classified as Pathogenic.
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:
Converted during submission to Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect due to protein misfolding and ER retention (Tamarappoo et al., 1998; Leduc-Nadeau et al., 2010); 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: 10564236, 10228154, 20403973, 11374071, 11076974, 14593099, 10997928, 7537761, 7524315, 15509592, 8140421, 9593782)
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017828). Different missense changes at the same codon (p.Arg187Gly, p.Arg187His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035695, VCV001481897). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 187 of the AQP2 protein (p.Arg187Cys). This variant is present in population databases (rs104894328, gnomAD 0.008%). This missense change has been observed in individuals with nephrogenic diabetes insipidus (NDI) in a family and also has been observed as homozygous or in combination with another AQP2 variant in individuals affected with NDI (PMID: 7524315, 20403973). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17828). 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) performed at Invitae indicates that this missense variant is expected to disrupt AQP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AQP2 function (PMID: 9593782, 10228154, 10564236, 11374071, 20403973). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| New autosomal recessive mutations in aquaporin-2 causing nephrogenic diabetes insipidus through deficient targeting display normal expression in Xenopus oocytes. | Leduc-Nadeau A | The Journal of physiology | 2010 | PMID: 20403973 |
| Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. | de Mattia F | Journal of the American Society of Nephrology : JASN | 2005 | PMID: 16120822 |
| Glycosylation is important for cell surface expression of the water channel aquaporin-2 but is not essential for tetramerization in the endoplasmic reticulum. | Hendriks G | The Journal of biological chemistry | 2004 | PMID: 14593099 |
| Functionality of aquaporin-2 missense mutants in recessive nephrogenic diabetes insipidus. | Marr N | Pflugers Archiv : European journal of physiology | 2001 | PMID: 11374071 |
| Consequences of aquaporin 2 tetramerization for genetics and routing. | Kamsteeg EJ | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2000 | PMID: 11143979 |
| The subcellular localization of an aquaporin-2 tetramer depends on the stoichiometry of phosphorylated and nonphosphorylated monomers. | Kamsteeg EJ | The Journal of cell biology | 2000 | PMID: 11076974 |
| Importance of aquaporin-2 expression levels in genotype -phenotype studies in nephrogenic diabetes insipidus. | Kamsteeg EJ | American journal of physiology. Renal physiology | 2000 | PMID: 10997928 |
| Functional analysis of aquaporin-2 mutants associated with nephrogenic diabetes insipidus by yeast expression. | Shinbo I | The American journal of physiology | 1999 | PMID: 10564236 |
| An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. | Kamsteeg EJ | The EMBO journal | 1999 | PMID: 10228154 |
| Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. | Tamarappoo BK | The Journal of clinical investigation | 1998 | PMID: 9593782 |
| Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. | Deen PM | The Journal of clinical investigation | 1995 | PMID: 7537761 |
| Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. | van Lieburg AF | American journal of human genetics | 1994 | PMID: 7524315 |
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Text-mined citations for rs104894328 ...
HelpThese 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 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.