U.S. flag

An official website of the United States government

NM_000053.4(ATP7B):c.3190G>A (p.Glu1064Lys) AND Wilson disease

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Oct 13, 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:
RCV000665883.9

Allele description [Variation Report for NM_000053.4(ATP7B):c.3190G>A (p.Glu1064Lys)]

NM_000053.4(ATP7B):c.3190G>A (p.Glu1064Lys)

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.3190G>A (p.Glu1064Lys)
HGVS:
  • NC_000013.11:g.51944162C>T
  • NG_008806.1:g.72333G>A
  • NM_000053.4:c.3190G>AMANE SELECT
  • NM_001005918.3:c.2569G>A
  • NM_001243182.2:c.2857G>A
  • NM_001330578.2:c.2956G>A
  • NM_001330579.2:c.2938G>A
  • NP_000044.2:p.Glu1064Lys
  • NP_001005918.1:p.Glu857Lys
  • NP_001230111.1:p.Glu953Lys
  • NP_001317507.1:p.Glu986Lys
  • NP_001317508.1:p.Glu980Lys
  • NC_000013.10:g.52518298C>T
  • NM_000053.3:c.3190G>A
  • p.Glu1064Lys
Protein change:
E1064K
Links:
dbSNP: rs376910645
NCBI 1000 Genomes Browser:
rs376910645
Molecular consequence:
  • NM_000053.4:c.3190G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005918.3:c.2569G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243182.2:c.2857G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330578.2:c.2956G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330579.2:c.2938G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000790078Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Likely pathogenic
(Mar 6, 2017)
unknownclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV001977269Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 10, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002059847Centogene AG - the Rare Disease Company
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 18, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002233901Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 13, 2023)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004562683ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)
Pathogenic
(Oct 13, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis.

Lepori MB, Zappu A, Incollu S, Dessì V, Mameli E, Demelia L, Nurchi AM, Gheorghe L, Maggiore G, Sciveres M, Leuzzi V, Indolfi G, Bonafé L, Casali C, Angeli P, Barone P, Cao A, Loudianos G.

Mol Cell Probes. 2012 Aug;26(4):147-50. doi: 10.1016/j.mcp.2012.03.007. Epub 2012 Mar 29.

PubMed [citation]
PMID:
22484412

Revised King's College score for liver transplantation in adult patients with Wilson's disease.

Petrasek J, Jirsa M, Sperl J, Kozak L, Taimr P, Spicak J, Filip K, Trunecka P.

Liver Transpl. 2007 Jan;13(1):55-61.

PubMed [citation]
PMID:
17154398
See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000790078.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV001977269.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Centogene AG - the Rare Disease Company, SCV002059847.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002233901.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu1064 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15205462, 15723329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ATP7B function (PMID: 18203200, 22240481). 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. ClinVar contains an entry for this variant (Variation ID: 550969). This variant is also known as p.Glu1065Lys. This missense change has been observed in individual(s) with Wilson disease (PMID: 8533760, 15571607, 17272994). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs376910645, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1064 of the ATP7B protein (p.Glu1064Lys).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004562683.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ATP7B c.3190G>A; p.Glu1064Lys variant (rs376910645) is reported in the literature in multiple individuals affected with Wilson disease (Balashova 2020, Figus 1995, Firneisz 2004). This variant is also reported in ClinVar (Variation ID: 550969). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another amino acid substitution at this codon (c.3191A>C; p.Glu1064Ala) has been reported in individuals with Wilson disease and is considered pathogenic (Ala 2005, Morgan 2004, Shah 1997). Functional analyses of the variant protein show that transport activity is ablated (Huster 2012, His 2008). Computational analyses predict that this variant is deleterious (REVEL: 0.958). Based on available information, this variant is considered to be pathogenic. References: Ala A et al. Wilson disease in septuagenarian siblings: Raising the bar for diagnosis. Hepatology. 2005 Mar;41(3):668-70. PMID: 15723329. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995 Dec;57(6):1318-24. PMID: 8533760. Firneisz G et al. The other mutation is found: follow-up of an exceptional family with Wilson disease. Am J Gastroenterol. 2004 Dec;99(12):2504-5. PMID: 15571607. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Hsi G et al. Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system. Hum Mutat. 2008 Apr;29(4):491-501. PMID: 18203200. Morgan CT et al. The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem. 2004 Aug 27;279(35):36363-71. PMID: 15205462. Shah 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024