VCV000010840.5 - ClinVar

NM_000054.7(AVPR2):c.337C>T (p.Arg113Trp)

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.

(3)

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_000054.7(AVPR2):c.337C>T (p.Arg113Trp)

Variation ID: 10840 Accession: VCV000010840.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 153905843 (GRCh38) [ NCBI UCSC ] X: 153171297 (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	Jul 25, 2015	Feb 14, 2024	Jan 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000054.7:c.337C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000045.1:p.Arg113Trp	missense
NM_001146151.3:c.337C>T	NP_001139623.1:p.Arg113Trp	missense
NC_000023.11:g.153905843C>T
NC_000023.10:g.153171297C>T
NG_008687.1:g.5870C>T
NG_013220.1:g.25418G>A
LRG_716:g.5870C>T
LRG_716t1:c.337C>T	LRG_716p1:p.Arg113Trp
	P30518:p.Arg113Trp

... more HGVS ... less HGVS

Protein change

R113W

Other names

Canonical SPDI

NC_000023.11:153905842:C:T

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), exomes 0.00001

Links

ClinGen: CA255567 UniProtKB: P30518#VAR_003524 OMIM: 300538.0006 dbSNP: rs28935496 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.
AVPR2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	317	579

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.
Diabetes insipidus, nephrogenic, X-linked	Pathogenic (2)	criteria provided, single submitter	-	RCV000011587.6
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2023	RCV003556000.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Diabetes insipidus, nephrogenic, X-linked (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003845987.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Publications: PubMed (1) PubMed: 30976394 Comment: A Hemizygote Missense variant c.337C>T in Exon 3 of the AVPR2 gene that results in the amino acid substitution p.Arg113Trp was identified. The observed variant … (more) A Hemizygote Missense variant c.337C>T in Exon 3 of the AVPR2 gene that results in the amino acid substitution p.Arg113Trp was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 10840). This variant was reported among the patients for nephrogenic diabetes insipidus (Sonia Sharma et al., 2019). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Jan 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004299151.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 33009446‚ 7984150‚ 8104196‚ 10770218‚ 29594432‚ 34101133 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg113 amino acid residue in AVPR2. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg113 amino acid residue in AVPR2. Other variant(s) that disrupt this residue have been observed in individuals with AVPR2-related conditions (PMID: 33009446; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 7984150). 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 AVPR2 protein function. ClinVar contains an entry for this variant (Variation ID: 10840). This missense change has been observed in individuals with X-linked recessive nephrogenic diabetes insipidus (PMID: 8104196, 10770218, 29594432, 34101133). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 113 of the AVPR2 protein (p.Arg113Trp). (less)
Pathogenic (May 27, 1993)	no assertion criteria provided Method: literature only	DIABETES INSIPIDUS, NEPHROGENIC, 1, X-LINKED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031819.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 26, 2021	Publications: PubMed (3) PubMed: 4886456‚ 5309332‚ 8479490 Comment on evidence: In affected members of a family studied by Bode and Crawford (1969) and Bode and Miettinen (1970) with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Holtzman … (more) In affected members of a family studied by Bode and Crawford (1969) and Bode and Miettinen (1970) with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Holtzman et al. (1993) identified a C-to-T transition in the AVPR2 gene, resulting in an arg113-to-trp (R113W) substitution. Most of the family members had been longtime residents of a town in central Maine. The finding of various mutations in North American patients with nephrogenic diabetes insipidus rendered the 'Hopewell hypothesis' of a founder mutation (Bode and Crawford, 1969) untenable. (less)

Comment:

A Hemizygote Missense variant c.337C>T in Exon 3 of the AVPR2 gene that results in the amino acid substitution p.Arg113Trp was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 10840). This variant was reported among the patients for nephrogenic diabetes insipidus (Sonia Sharma et al., 2019). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg113 amino acid residue in AVPR2. Other variant(s) that disrupt this residue have been observed in individuals with AVPR2-related conditions (PMID: 33009446; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 7984150). 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 AVPR2 protein function. ClinVar contains an entry for this variant (Variation ID: 10840). This missense change has been observed in individuals with X-linked recessive nephrogenic diabetes insipidus (PMID: 8104196, 10770218, 29594432, 34101133). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 113 of the AVPR2 protein (p.Arg113Trp).

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
Novel AVPR2 mutations and clinical characteristics in 28 Chinese families with congenital nephrogenic diabetes insipidus.	Li Q	Journal of endocrinological investigation	2021	PMID: 34101133
Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation.	Prosperi F	Scientific reports	2020	PMID: 33009446
Long-term outcome in inherited nephrogenic diabetes insipidus.	Sharma S	Clinical kidney journal	2018	PMID: 30976394
Novel and recurrent variants in AVPR2 in 19 families with X-linked congenital nephrogenic diabetes insipidus.	Joshi S	European journal of pediatrics	2018	PMID: 29594432
Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families.	Pasel K	The Journal of clinical endocrinology and metabolism	2000	PMID: 10770218
An extracellular congenital nephrogenic diabetes insipidus mutation of the vasopressin receptor reduces cell surface expression, affinity for ligand, and coupling to the Gs/adenylyl cyclase system.	Birnbaumer M	Molecular endocrinology (Baltimore, Md.)	1994	PMID: 7984150
Brief report: a molecular defect in the vasopressin V2-receptor gene causing nephrogenic diabetes insipidus.	Holtzman EJ	The New England journal of medicine	1993	PMID: 8479490
X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.	Bichet DG	The Journal of clinical investigation	1993	PMID: 8104196
Nephrogenic diabetes insipidus: absence of close linkage with Xg.	Bode HH	American journal of human genetics	1970	PMID: 5309332
Nephrogenic diabetes insipidus in North America. The Hopewell hypothesis.	Bode HH	The New England journal of medicine	1969	PMID: 4886456

Text-mined citations for rs28935496 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000054.7(AVPR2):c.337C>T (p.Arg113Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28935496 ...