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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000790078	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 6, 2017)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15571607, 18203200, 8533760, 22484412, 17154398, 23789284, 15967699, 22240481, 17272994 Citation Link,
SCV001977269	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059847	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 18, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002233901	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 13, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15205462, 15723329, 18203200, 22240481, 8533760, 15571607, 17272994, 28492532
SCV004562683	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 13, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

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

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

#	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 Genome-Nilou Lab, SCV001977269.1

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

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

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

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

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

#	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

Last Updated: Sep 29, 2024

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