13-51946438-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2906G>A(p.Arg969Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 7.86

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Extracellular (size 29) in uniprot entity ATP7B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 13-51946438-C-T is Pathogenic according to our data. Variant chr13-51946438-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946438-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.2906G>A	p.Arg969Gln	missense_variant	Exon 13 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.2906G>A	p.Arg969Gln	missense_variant	Exon 13 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249470

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3, PM5, PM3_VSTR,PM2_SUP,PP3,PP4 -

Nov 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant summary: The ATP7B c.2906G>A (p.Arg969Gln) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type_ATPase_Cu-like domain and 3/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional studies, where R969Q was shown to markedly affect copper transport and lead to hyperphosphorylation (Huster, 2012). This variant was found in 10/277242 control chromosomes at a frequency of 0.000036, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals with clinically and biochemically confirmed Wilsons disease (WD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Feb 01, 2013

Arcensus

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 969 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant partially disrupts copper transport and hyperphosphorylation (PMID: 22240481). This variant has been reported in individuals affected with Wilson disease (PMID: 8533760, 9482578, 9801873, 10447265, 10544227, 11216666, 11690702, 12885331, 15523622, 15967699, 17264425, 17325640, 18286826, 19172127, 20082719, 20517649, 22308153, 26580967, 26799313, 26819605, 27706781, 30230192, 30702195, 33640437). In a number of these individuals, this variant was reported in the homozygous state or in the compound heterozygous state (PMID: 8533760, 9482578, 12885331, 15523622, 17264425, 17325640, 18286826, 19172127, 22308153, 30702195). This variant has been identified in 10/280870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 969 of the ATP7B protein (p.Arg969Gln). This variant is present in population databases (rs121907996, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8533760, 9801873, 17325640, 20517649, 22308153, 26819605). This variant is also known as p.Arg970Gln. ClinVar contains an entry for this variant (Variation ID: 3860). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic. -

Jan 02, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg969Gln variant in ATP7B has been reported in >20 probands with Wilson disease, including at least 13 homozygotes and 14 compound heterozygotes (Ferenci 2014), and has been reported in ClinVar (Variation ID 3860). It has also been identified in 3/30600 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson Disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Supporting, PP3. -

Dec 20, 2021

Credence Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The specific mutation is seen to affect the ATP7B in certain populations and in turn lowering ceruloplasmin levels https://www.nature.com/articles/s41598-021-87000-9 -

not provided

Pathogenic:3

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -

Jan 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R969Q pathogenic variant in the ATP7B gene has been reported previously, using alternate nomenclature A970Q, in association with Wilson disease when present in the homozygous state or when in trans with another disease-causing variant (Figus et al., 1995). The R969Q variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R969Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show R969Q had a significant decrease in copper uptake compared to wild type (Huster et al., 2012). Missense variants in the same and nearby residues (R969W, A971V, T974M) have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R969Q as a pathogenic variant. -

ATP7B-related disorder

Pathogenic:1

Nov 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP7B c.2906G>A variant is predicted to result in the amino acid substitution p.Arg969Gln. This variant has been reported in the homozygous state and in the heterzogyous state with a second pathogenic variant in multiple individuals with Wilson disease (see for example, Figus et al. 1995. PubMed ID: 8533760; Panagiotakaki et al. 2004. PubMed ID: 15523622; Zhang et al. 2022. PubMed ID: 35220961). Although one in vitro study found the p.Arg969Gln variant had copper transport activity similar to wild type (Schushan et al. 2012. PubMed ID: 22692182), two other studies have reported moderate to complete loss of transport function (Huster et al. 2012. PubMed ID: 22240481; Das et al. 2022. PubMed ID: 35762218). Furthermore, ATP7A protein with the p.Arg969Gln variant has been shown to have reduced expression relative to wild type and improper cellular localization to the endoplasmic reticulum (Das et al. 2022. PubMed ID: 35762218). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Of note, a different missense variant at the same amino acid position (p.Arg969Trp) has also been reported in an individual with Wilson disease (Lepori et al. 2007. PubMed ID: 17949296). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

D;D;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.20

N;.;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;N;N;N;N;.

REVEL

Pathogenic

0.75

Sift

Benign

0.38

T;T;T;T;T;.

Sift4G

Benign

0.44

T;T;T;T;T;T

Polyphen

1.0

D;D;D;B;B;B

Vest4

0.91

MutPred

0.87

Gain of helix (P = 0.1736);.;.;.;.;.;

MVP

0.92

MPC

0.40

ClinPred

0.50

GERP RS

5.2

Varity_R

0.27

gMVP

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over