rs137853284

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2332C>T(p.Arg778Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,062 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R778L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 1.89

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 18 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity ATP7B_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-51958333-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 13-51958334-G-A is Pathogenic according to our data. Variant chr13-51958334-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 456553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958334-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2332C>T	p.Arg778Trp	missense_variant	8/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2332C>T	p.Arg778Trp	missense_variant	8/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

249436

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000759

AC:

111

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000908

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000619

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000254

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This variant was detected in multiple affected individuals as homozygous or as compound heterozygous (in trans) with a likely pathogenic or pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 9311736, 10502777, 17160357, 30120852, 23567103, 36096368, 25130000, 16207219, 22735241, 20453399, 23518715). It has been reported to co-segregate with Wilson disease in multiple families (PMID: 23518715). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional analysis suggests that this variant results in a deleterious effect on the protein (PMID: 17160357). Other missense substitutions at this amino acid residue have been previously reported in individual(s) with Wilson disease and classified as pathogenic (ClinVar variant IDs: 3852, 550914, 156283), which supports the functional importance of this position. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2022	The ATP7B c.2332C>T; p.Arg778Trp variant (rs137853284) is reported in homozygous and compound heterozygous state in several individuals with Wilson disease (Butler 2001, Coffey 2013, Kumar 2007, Shah 1997) and is described as segregating with disease (Coffey 2013). The variant is listed in the ClinVar database (Variation ID: 456553) and in the general population with an overall allele frequency of 0.005% (13/249,436 alleles) in the Genome Aggregation Database. The arginine at codon 778 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.877). In support of this prediction, this variant has been shown to have reduced function (Kumar 2007). Additionally, other amino acid substitutions at this codon (p.Arg778Gln, p.Arg778Gly, p.Arg778Leu) have been reported in individuals with Wilson disease and are considered pathogenic (Dong 2016, Forbes 1998, Kumar 2007, Schushan 2012). Considering available information, this variant is classified as pathogenic. References: Butler P et al. Molecular diagnosis of Wilson disease. Mol Genet Metab. 2001 Mar;72(3):223-30. PMID: 11243728. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Forbes JR and Cox DW. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet. 1998 Dec;63(6):1663-74. PMID: 9837819. Kumar S et al. Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: correlation between genotype/phenotype/copper ATPase activity. Mol Cell Biochem. 2007 Jan;294(1-2):1-10. PMID: 17160357. Schushan M et al. A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. Metallomics. 2012 Jul;4(7):669-78. PMID: 22692182. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Arg778Trp variant in ATP7B has been reported in several individuals with Wilson disease, including at least 4 homozygotes and 9 compound heterozygotes (Coffey 2013, Dufernez 2013, Okada 2000). This variant has also been identified in 0.01% (3/15482) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2017	Variant summary: The ATP7B c.2332C>T (p.Arg778Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/120374 control chromosomes at a frequency of 0.0000415, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant is in the P-type ATPase A domain (IPR008250) with one study (Kumar_MCB_2007) showing decreased copper stimulated ATPase activity with this variant compared to WT and biochemical finding suggesting deleterious effect (Kumar, 2007; Dufernez, 2013). The variant was identified in multiple affected individuals homozygously or in compound heterozygosity in patients with clinically and biochemically confirmed Wilsons disease (WD). Multiple family studies showed segregation of this variant with WD. The codon Arg778 appears to be a mutational hot-spot, as other alteration, such as p.R778Q, p.R778G and p.R778L have been reported in patients with WD. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 778 of the ATP7B protein (p.Arg778Trp). This variant is present in population databases (rs137853284, gnomAD 0.02%). This missense change has been observed in individual(s) with Kayser-Fleischer rings and low serum ceruloplasmin, findings that are highly specific for Wilson disease (PMID: 17160357). ClinVar contains an entry for this variant (Variation ID: 456553). 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 ATP7B protein function with a positive predictive value of 80%. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10790207, 11405812, 16283883, 19937698, 20517649, 20931554, 21682854, 23333878, 27022412). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	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: 9837819, 17160357, 23333878, 24253677, 22692182, 10502776, 11093740, 10790207, 11721763, 10502777, 9311736, 9671269, 26207595, 28265897, 30120852, 32043565, 30275481, 31589614, 33726816, 33159804) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 06, 2021	PS4, PM1, PM2, PM5, PP4 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

The p.R778W pathogenic mutation (also known as c.2332C>T), located in coding exon 8 of the ATP7B gene, results from a C to T substitution at nucleotide position 2332. The arginine at codon 778 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been seen in trans with another mutation in four individuals from two unrelated families who all fulfilled diagnostic criteria (developed at the 8th International Meeting on Wilson disease) for Wilson disease (Coffey AJ, et al. Brain 2013 May; 136(Pt 5):1476-87). In addition, mutations affecting the same arginine reside at codon 778, p.R778L and p.R778G, have been reported in the literature (Chuang LM, et al. J. Med. Genet. 1996 Jun; 33(6):521-3). Based on the supporting evidence, p.R778W is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.5

D;D;.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.97

MVP

0.99

MPC

0.38

ClinPred

1.0

GERP RS

3.5

Varity_R

0.96

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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