rs28942074

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000053.4(ATP7B):c.2333G>T(p.Arg778Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,614,178 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. R778Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:2

Conservation

PhyloP100: 7.85

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 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-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 13-51958333-C-A is Pathogenic according to our data. Variant chr13-51958333-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958333-C-A is described in Lovd as [Pathogenic]. Variant chr13-51958333-C-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.2333G>T	p.Arg778Leu	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.2333G>T	p.Arg778Leu	missense_variant	8/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000136

AC:

AN:

249404

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00189

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00154

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000503

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14Other:2

Pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2020	The p.Arg778Leu variant in ATP7B is the most common pathogenic variant causative for Wilson disease in Asian populations, with many homozygous and compound heterozygous probands reported and at least 4 segregations in affected relatives from 4 families (Hua 2016, Shimizu 1999, Shiono 2001, Wu 2001, Yoo 2002). It has also been reported in by clinical laboratories in ClinVar (Variation ID 3852) and has been identified in 0.189% (37/19538) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is consistent with a recessive carrier frequency. In vitro functional studies have shown that this variant results in mislocalization of the protein and abnormal copper transport (Forbes 1998, van den Berghe 2009, Zhu 2015). Computational prediction tools and conservation analyses suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 778 of the ATP7B protein (p.Arg778Leu). This variant is present in population databases (rs28942074, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10453196, 11405812, 25086856, 25988284, 27398169, 28212618). ClinVar contains an entry for this variant (Variation ID: 3852). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 9837819, 10942420, 19937698). 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: 11243728, 11479773, 16998622, 17160357, 23518715). 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, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_000053.3(ATP7B):c.2333G>T(R778L) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 17587212 and 11405812. Classification of NM_000053.3(ATP7B):c.2333G>T(R778L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2022	The ATP7B c.2333G>T; p.Arg778Leu variant (rs28942074) is a common pathogenic variant in Asian populations found homozygous and compound heterozygous in several individuals affected with Wilson disease (Li 2013, Wu 2001, Xiao 2019). Functional analyses of the variant protein show reduced expression, defective copper excretion, and subcellular mislocalization (van den Berghe 2009, Zhu 2015). This variant is reported in ClinVar (Variation ID: 3852) and is found in East Asian population with an allele frequency of 0.2% (37/19538 alleles) in the Genome Aggregation Database. The arginine at codon 778 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.947). Based on available information, this variant is considered to be pathogenic. References: Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. PMID: 23235335. van den Berghe PV et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology. 2009 Dec;50(6):1783-95. PMID: 19937698. Wu ZY et al. Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Arch Neurol. 2001 Jun;58(6):971-6. PMID: 11405812. Xiao H et al. Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease. Digestion. 2019;99(4):319-326. PMID: 30384382. Zhu M et al. Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion. Mol Cell Neurosci. 2015 Jul;67:31-6. PMID: 26032686. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2017	Variant summary: The ATP7B c.2333G>T (p.Arg778Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that lies within the P-type ATPase, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/246194 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been identified in numerous patients as compound heterozygous and homozygous, and multiple other mutations have been reported in patients at the same codon (R778L, R778G, R778Q, and R778W), suggesting the site is a mutational hotspot. Functional studies in yeast showed that copper transport was severely impaired and the variant protein was mislocalized to the ER and/or lysosomes (Forbes_2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ATP7B c.2333G>T (p.Arg778Leu) variant is widely reported in the literature as a common variant in Wilson disease (WD) in Asian populations. Across a selection of available literature, the p.Arg778Leu variant has been identified in 114 WD patients of Chinese, Japanese, and Korean ancestry, including 32 homozygotes, 57 compound heterozygotes, and 32 heterozygotes. The variant was also found in a heterozygous state in six unaffected parents of probands (Thomas et al. 1995; Kusuda et al. 2000; Wu et al. 2001; Yoo et al. 2002; Bae et al. 2009; Hua et al. 2016, Zong et al. 2016). Wu et al. (2001) found that patients who were homozygous for the p.Arg778Leu variant had an earlier age of onset (14.2 years vs. 22.0 years) and neurologic rather than hepatic symptoms at onset when compared to compound heterozygotes. The p.Arg778Leu variant was absent from 60 controls (Wu et al. 2001), but is reported at a frequency of 0.00232 in the East Asian population of the Exome Aggregation Consortium. Van den Berghe et al. (2009) demonstrated reduced protein expression and mislocalization to the endoplasmic reticulum of the p.Arg778Leu variant protein compared to wild type. Zhu et al. (2015) showed that the p.Arg778Leu variant caused reduced copper excretion and impaired the protective effect of the wild type protein on cell exposed to excess copper. Based on the collective evidence, the p.Arg778Leu variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2022	Functional expression studies with the R778L variant in yeast showed defective rescue of normal copper transport function (Forbes et al., 1998). Expression studies in CHO cells demonstrated this variant disrupted both the normal localization and trafficking of ATP7B (Zhu et al., 2015); 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: 24253677, 24878384, 26782526, 27398169, 30366773, 16998622, 11479773, 23518715, 19419418, 34458581, 34666712, 29979436, 35357466, 9837819, 11405812, 19937698, 10942420, 23235335, 10721669, 25086856, 19783880, 22692182, 7626145, 26032686, 14986826, 21796144, 23843956, 25988284, 12812649, 28212618, 29907136, 17587212, 11243728, 17160357, 10453196, 9554743, 16133174, 29961769, 30655162, 31010795, 29181760, 30384382, 30558096, 31474638, 31637888, 31783295, 31804371, 31743419, 30275481, 32005694, 34539730, 34240825, 34345444, 33096383, 34324271, 33668890, 32911910, 33763395, 32794656) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2014

The p.R778L pathogenic mutation (also known as c.2333G>T), located in coding exon 8 of the ATP7B gene, results from a G to T substitution at nucleotide position 2333. The arginine at codon 778 is replaced by leucine, an amino acid with dissimilar properties.This pathogenic alteration has been observed in both the homozygous and compound heterozygous state in patients with a biochemical diagnosis of Wilson disease (Thomas GR, et al. Nat. Genet. 1995;9(2):210-7). Functional studies have determined that this mutation disrupts normal localization of the ATP7B protein, has reduced copper transport ability, and causes the affected protein to fail to localize into the Golgi apparatus, possibly due to misfolding (Forbes JR, et al. Hum. Mol. Genet. 2000;9(13):1927-35 and van den Berghe PV, et al. Hepatology 2009;50(6):1783-95). In addition, population studies have found this alteration to be a founder mutation in several Asian populations (Gu S, et al. PLoS ONE 2013;8(7):e66526 and Hui J, et al. World J Pediatr 2013;9(4):361-4). Based on the supporting evidence, p.R778L is interpreted as a disease-causing mutation. -

ATP7B-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The ATP7B c.2333G>T variant is predicted to result in the amino acid substitution p.Arg778Leu. This variant has been reported to be causative for Wilson disease both in the homozygous state and in the compound heterozygous state with a second pathogenic variant (see for example Thomas et al. 1995. PubMed ID: 7626145; Chuang et al. 1996. PubMed ID: 8782057; Hua et al. 2016. PubMed ID: 27398169). This variant is reported to be a common pathogenic variant in Asian populations (Thomas et al. 1995. PubMed ID: 7626145; Weiss et al. 2016. PubMed ID: 20301685). Alternate nucleotide changes affecting the same amino acid (p.Arg778Gln, p.Arg778Gly, p.Arg778Trp) have been reported in individuals with Wilson disease (Figus et al. 1995. PubMed ID: 8533760; Chuang et al. 1996. PubMed ID: 8782057; Shah et al. 1997. PubMed ID: 9311736). This variant has been reported 37 times among ~281,000 alleles (~0.01%) in a large population database, but is enriched in the East Asian population (https://gnomad.broadinstitute.org/variant/13-52532469-C-A). In ClinVar, this variant in interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/3852/). Taken together, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.6

D;D;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;B;D;D

Vest4

0.95

MutPred

0.93

Loss of MoRF binding (P = 0.04);.;.;Loss of MoRF binding (P = 0.04);

MVP

0.99

MPC

0.41

ClinPred

0.38

GERP RS

5.4

Varity_R

0.94

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