NM_000053.4(ATP7B):c.2333G>A (p.Arg778Gln) AND Wilson disease

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Dec 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000665805.14

Allele description [Variation Report for NM_000053.4(ATP7B):c.2333G>A (p.Arg778Gln)]

NM_000053.4(ATP7B):c.2333G>A (p.Arg778Gln)

Gene:

ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_000053.4(ATP7B):c.2333G>A (p.Arg778Gln)

HGVS:

NC_000013.11:g.51958333C>T
NG_008806.1:g.58162G>A
NM_000053.4:c.2333G>AMANE SELECT
NM_001005918.3:c.1870-726G>A
NM_001243182.2:c.2000G>A
NM_001330578.2:c.2122-726G>A
NM_001330579.2:c.2081G>A
NP_000044.2:p.Arg778Gln
NP_001230111.1:p.Arg667Gln
NP_001317508.1:p.Arg694Gln
NC_000013.10:g.52532469C>T
NM_000053.3:c.2333G>A

Protein change:

R667Q

Links:

dbSNP: rs28942074

NCBI 1000 Genomes Browser:

rs28942074

Molecular consequence:

NM_001005918.3:c.1870-726G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001330578.2:c.2122-726G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000053.4:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2000G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2081G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Wilson disease (WND)
Synonyms:: Wilson's disease; Hepatolenticular degeneration
Identifiers:: MONDO: MONDO:0010200; MedGen: C0019202; Orphanet: 905; OMIM: 277900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000789984	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Apr 24, 2017)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 21796144, 9837819, 24878384, 23235335, 8782057, 17587212, 11043508, 27022412, 17949296 Citation Link,
SCV000918605	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 28, 2018)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11405812, 24878384, 17587212, 9837819, 27982432, 20931554, 27022412, 24094725, 17949296, 8782057 Citation Link,
SCV001402302	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 20931554, 21796144, 27022412, 9837819, 10453196, 11243728, 11405812, 11479773, 16998622, 17160357, 20517649, 21682854, 23333878, 23518715, 25086856, 25988284, 27398169, 28212618, 28492532
SCV001459729	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001977324	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004176463	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216313	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004845534	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 30, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 8782057, 9837819, 11043508, 11405812, 17587212, 17949296, 20931554, 21796144, 23235335, 24094725, 24878384, 27022412, 28212618, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease.

Cheng N, Wang H, Wu W, Yang R, Liu L, Han Y, Guo L, Hu J, Xu L, Zhao J, Han Y, Liu Q, Li K, Wang X, Chen W.

Clin Genet. 2017 Jul;92(1):69-79. doi: 10.1111/cge.12951. Epub 2017 Feb 16.

PubMed [citation]

PMID:: 27982432

Molecular analysis and diagnosis in Japanese patients with Wilson's disease.

Shimizu N, Nakazono H, Takeshita Y, Ikeda C, Fujii H, Watanabe A, Yamaguchi Y, Hemmi H, Shimatake H, Aoki T.

Pediatr Int. 1999 Aug;41(4):409-13.

PubMed [citation]

PMID:: 10453196

See all PubMed Citations (28)

Details of each submission

From Counsyl, SCV000789984.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918605.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: ATP7B c.2333G>A (p.Arg778Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247080 control chromosomes (gnomAD and publications). c.2333G>A has been reported in the literature in multiple individuals affected with Wilson Disease (Cheng_2017, Dong_2016, Lu_2014, Mukherjee_2014, Wan_2010, Lepori_2007, Park_2007, Wu_2001, Chuang_1996). Individuals who are homozygous for the variant have been reported to present with neurological and hepato-neurological symptoms (Wan_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence indicate a damaging impact of the variant on protein function; specifically, the variant caused reduced copper bound holo-Fet3p activity in ccc2 mutant yeast and only partially rescued mutant yeast in complementation assay (Forbes_1998). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Additionally, a different variant at the same nucleotide and codon position has been described as a common pathogenic variant associated with Wilson disease (c.2333G>T, p.Arg778Leu), especially in the Asian population, supporting the functional importance of this position. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001402302.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 778 of the ATP7B protein (p.Arg778Gln). This variant is present in population databases (rs28942074, gnomAD 0.03%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11405812, 20931554, 21796144, 27022412). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550914). 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). 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: 10453196, 11243728, 11405812, 11479773, 16998622, 17160357, 20517649, 21682854, 23333878, 23518715, 25086856, 25988284, 27398169, 28212618). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001459729.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001977324.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004176463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense c.2333G>A (p.Arg778Gln) variant in ATP7B gene has been reported previously in multiple individuals affected with Wilson disease (Dong et al. 2016; Yu et al. 2017). Experimental studies have shown that this missense change affects ATP7B function and might result in a milder form of Wilson disease (Forbes & Cox 1998). The p.Arg778Gln variant is reported with an allele frequency of 0.003% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Arg778Gln in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 778 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Another variant [p.Arg778Leu] at this residue has previously been classified as pathogenic. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004216313.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004845534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (14)

Description

This missense variant replaces arginine with glutamine at codon 778 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). Studies conducted in yeast have shown that this variant disrupted function in a complementation assay and caused temperature sensitivity (PMID: 9837819). This variant has been reported in many individuals affected with Wilson disease (PMID: 8782057, 11043508, 11405812, 17587212, 17949296, 20931554, 21796144, 23235335, 24094725, 24878384, 27022412, 28212618) and in an unaffected control (PMID: 11043508). In several of these individuals, this variant was reported in the homozygous state or compound heterozygous state with a know pathogenic variant in the same gene (PMID: 11405812, 20931554, 24878384, 27022412, 28212618). This variant has been identified in 8/249404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Apr 20, 2024

Relating variation to medicine