X-153905915-C-T

Variant names:

• chrX-153905915-C-T
• rs104894761
• NM_000054.7:c.409C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000054.7(AVPR2):​c.409C>T​(p.Arg137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,089,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.00
• Publications: 48 publications found

Genes affected

AVPR2 (HGNC:897): (arginine vasopressin receptor 2) This gene encodes the vasopressin receptor, type 2, also known as the V2 receptor, which belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. The gene expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. [provided by RefSeq, Jul 2008]

AVPR2 Gene-Disease associations (from GenCC):

• diabetes insipidus, nephrogenic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephrogenic syndrome of inappropriate antidiuresis

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• nephrogenic diabetes insipidus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000054.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153905916-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10855.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-153905915-C-T is Pathogenic according to our data. Variant chrX-153905915-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.409C>T	p.Arg137Cys	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.409C>T	p.Arg137Cys	missense_variant	Exon 3 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.466-104C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.409C>T	p.Arg137Cys	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3155G>A		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00000566 AC: 1 AN: 176550 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1089408 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 1 AN XY: 360556

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842080

Other (OTH) AF: 0.00 AC: 0 AN: 46042

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000733 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrogenic syndrome of inappropriate antidiuresis Pathogenic:4

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with nephrogenic diabetes insipidus (MIM#304800) and nephrogenic syndrome of inappropriate antidiuresis (MIM#300539), respectively (PMID: 27355191). (I) 0109 - This gene is known to be associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0253 - Variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (I) 0600 - Variant is located in the annotated transmembrane domain 3 (PMID: 15872203, 29546600). (I) 0702 - Comparable variants have strong previous evidence for pathogenicity. p.(Arg137Leu) has been shown to cause nephrogenic syndrome of inappropriate antidiuresis (ClinVar; PMID: 15872203, 29546600). p.(Arg137His) and p.(Arg137Gly) have been shown to cause nephrogenic diabetes insipidus (ClinVar; PMID: 8104196, 15872203, 27117808). (SP) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with nephrogenic syndrome of inappropriate antidiuresis (ClinVar, PMID: 15872203, 17229917, 29546600) (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed that this variant caused constitutive activation of the receptor with high levels of cAMP (PMID: 15872203). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 05, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010854, PMID:15872203). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20159941). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20159941). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035739, PMID:27117808,8104196,15872203). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93>=0.6, 3CNET: 0.921>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000057). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PP4+PM5+PS3 -

not provided Pathogenic:2

Dec 12, 2019

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that R137C results in constitutive activation of the AVP receptor with a 4-fold increase in basal cAMP production (Feldman et al., 2005; Tiulpakov et al., 2016; Ranieri et al., 2019); 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: 20159941, 16843086, 20631022, 19542240, 34645113, 21834801, 27355191, 17229917, 15872203, 18622631, 18753429, 32499611, 31486901, 26715131, 22154540, 29472987, 32486031) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;.;H;H
PhyloP100		2.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.0	.;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.99, 0.99
MutPred		0.97		Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104894761; hg19: chrX-153171369;