VCV000003848.92 - ClinVar

NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(40)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln)

Variation ID: 3848 Accession: VCV000003848.92

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.3 13: 51944145 (GRCh38) [ NCBI UCSC ] 13: 52518281 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000053.4:c.3207C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000044.2:p.His1069Gln	missense
NM_000053.3:c.[3207C>A]
NM_001005918.3:c.2586C>A	NP_001005918.1:p.His862Gln	missense
NM_001243182.2:c.2874C>A	NP_001230111.1:p.His958Gln	missense
NM_001330578.2:c.2973C>A	NP_001317507.1:p.His991Gln	missense
NM_001330579.2:c.2955C>A	NP_001317508.1:p.His985Gln	missense
NC_000013.11:g.51944145G>T
NC_000013.10:g.52518281G>T
NG_008806.1:g.72350C>A
	P35670:p.His1069Gln

... more HGVS ... less HGVS

Protein change

H1069Q, H958Q, H862Q, H991Q, H985Q

Other names

H714Q

Canonical SPDI

NC_000013.11:51944144:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00091

The Genome Aggregation Database (gnomAD) 0.00100

Links

ClinGen: CA220309 UniProtKB: P35670#VAR_000758 OMIM: 606882.0002 OMIM: 606882.0006 dbSNP: rs76151636 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATP7B		-	-	GRCh38 GRCh37	2926	3070

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Wilson disease	Pathogenic (31)	criteria provided, multiple submitters, no conflicts	May 6, 2024	RCV000004052.77
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000078049.50
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2021	RCV002321470.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593529.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Feb 06, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225992.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B Number of individuals with the variant: 24 Sex: mixed
Pathogenic (Mar 29, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Wilson disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967653.2 First in ClinVar: Aug 26, 2019 Last updated: Jul 06, 2020	Publications: PubMed (6) PubMed: 24897373‚ 19937698‚ 9887381‚ 8298641‚ 10051024‚ 11690702 Comment: The p.His1069Gln variant in ATP7B has been reported in numerous homozygous and compound heterozygous individuals with Wilson disease and is the most common variant identified … (more) The p.His1069Gln variant in ATP7B has been reported in numerous homozygous and compound heterozygous individuals with Wilson disease and is the most common variant identified in European patients (Tanzi 1993, Duc 1999, Ivanova-Smolenskaya 1999, Caca 2001, Cocos 2014). This variant has also been reported by clinical laboratories in ClinVar (Variation ID#3848) and been identified in 0.5% (53/10148) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is consistent with the known carrier frequency of Wilson disease. In vitro functional studies provide some evidence that the p.His1069Gln variant may result in reduced ATP7B protein expression (van den Berghe 2009) and computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease based upon its common biallelic occurrence in patients with this disease and functional evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. (less) Number of individuals with the variant: 3
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193833.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (4) PubMed: 9352458‚ 9887381‚ 11857545‚ 7626145 Comment: NM_000053.3(ATP7B):c.3207C>A(H1069Q) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9352458, 9887381, 11857545, and 7626145. Classification … (more) NM_000053.3(ATP7B):c.3207C>A(H1069Q) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9352458, 9887381, 11857545, and 7626145. Classification of NM_000053.3(ATP7B):c.3207C>A(H1069Q) 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. (less)
Pathogenic (May 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369212.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PP2,PP3,PP5.
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001480155.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Abnormal basal ganglia morphology (present) , Involuntary movements (present) Sex: male
Pathogenic (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001977266.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Mar 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502131.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (37) PubMed: 8298641‚ 31708252‚ 10406672‚ 28602929‚ 31589614‚ 30609409‚ 24897373‚ 18311837‚ 19306278‚ 21398519‚ 9887381‚ 11857545‚ 25333069‚ 22286624‚ 31980526‚ 22240481‚ 9654149‚ 22221592‚ 9214248‚ 22730635‚ 31664448‚ 28119449‚ 15205462‚ 29674751‚ 24909901‚ 18692069‚ 32043565‚ 32532207‚ 22692182‚ 32270360‚ 24253677‚ 28776642‚ 23430908‚ 19937698‚ 26286547‚ 33098801‚ 33100332 Number of individuals with the variant: 4 Secondary finding: no
Pathogenic (Aug 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002578021.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: ACMG categories: PS3,PM1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Elevated circulating hepatic transaminase concentration (present) Age: 40-49 years Sex: female Tissue: blood
Pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581615.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PP1_STR, PS3_MOD, PS4_MOD, PM3, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: unknown	3billion Accession: SCV004013840.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (3) PubMed: 21645214‚ 8298641‚ 22308153 Comment: The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.102%). In silico tool predictions suggest damaging … (more) The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.102%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.93). The the same nucleotide change resulting in the the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003848/PMID:8298641/3billion dataset). Different missense changes at the the same codon (p.His1069Arg, p.His1069Asn, p.His1069Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001069926/PMID: 21645214, 22308153). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Elevated circulating creatine kinase concentration (present) , Muscle weakness (present) , Bradykinesia (present) , Dysarthria (present)
Pathogenic (Aug 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026153.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS4, PP3, PM2_SUP, PS3
Pathogenic (Dec 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022016.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004845404.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (41) PubMed: 7626145‚ 8298641‚ 9214248‚ 9352458‚ 9654149‚ 9724794‚ 9887381‚ 10051024‚ 10406672‚ 10544227‚ 11857545‚ 12557139‚ 15967699‚ 16207219‚ 17717039‚ 18311837‚ 18692069‚ 19306278‚ 19937698‚ 21398519‚ 22221592‚ 22240481‚ 22286624‚ 22692182‚ 22720308‚ 22730635‚ 23430908‚ 24253677‚ 24897373‚ 24909901‚ 26286547‚ 28119449‚ 28776642‚ 29674751‚ 30026388‚ 30609409‚ 31708252‚ 32043565‚ 32270360‚ 32532207‚ 33098801 Comment: This missense variant replaces histidine with glutamine at codon 1069 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces histidine with glutamine at codon 1069 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). Functional studies have shown that this variant results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388). This variant has been reported in numerous homozygous and compound heterozygous individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9214248, 9352458, 9887381, 10051024, 10406672, 10544227, 11857545, 12557139, 15967699, 16207219, 18311837, 19306278, 22286624, 22221592, 22720308, 22730635, 23430908, 24897373, 26286547, 28776642, 30609409, 31708252, 32043565, 32270360, 32532207, 33098801) and has been shown to segregate with disease in family studies (PMID: 24897373, 31708252, 32043565, 32532207). Homozygosity for this variant is the most common cause of Wilson disease among patients of European ancestry (PMID: 7626145, 9724794, 9887381). This variant has been identified in 286/280766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 306
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199647.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Mar 07, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236509.2 First in ClinVar: Jul 03, 2015 Last updated: Jul 03, 2015
Pathogenic (Jan 23, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Wilson disease (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149696.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Pathogenic (Dec 05, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329091.6 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: Published functional studies show the H1069Q variant has significantly reduced ATP binding affinity and reduced protein stability, leading to impaired copper transport (Dmitriev et al., … (more) Published functional studies show the H1069Q variant has significantly reduced ATP binding affinity and reduced protein stability, leading to impaired copper transport (Dmitriev et al., 2011; Morgan et al., 2004; Rodriguez-Granillo et al., 2008; Chesi et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22692182, 25333069, 24897373, 22730635, 22240481, 28392828, 27641668, 28119449, 28776642, 30609409, 31028847, 28602929, 23430908, 19306278, 22286624, 30232804, 15024742, 23982005, 24253677, 24909901, 9887381, 9654149, 18692069, 22221592, 8298641, 11857545, 15967699, 27122662, 26660341, 18311837, 10406672, 19937698, 26286547, 16567646, 28717664, 23159873, 22763723, 18855987, 9724794, 29674751, 15205462, 21398519, 31708252, 31664448, 31980526, 32043565, 32532207) (less)
Pathogenic (Dec 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV002051776.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Publications: PubMed (6) PubMed: 11690702‚ 12557139‚ 15967699‚ 19937698‚ 7626145‚ 9724794 Comment: ATP7B c.3207C>A has been identified in the homozygous or compound heterozygous state in many individuals with Wilson disease. It is the most common pathogenic ATP7B … (more) ATP7B c.3207C>A has been identified in the homozygous or compound heterozygous state in many individuals with Wilson disease. It is the most common pathogenic ATP7B variant associated with Wilson disease in populations of European origin. This variant (rs76151636) is present in a large population dataset (gnomAD: 286/280766 total alleles; 0.1019%; no homozygotes) and has been reported in ClinVar. Functional studies demonstrate that this substitution results in mislocalization and increased degradation of the ATP7B protein in cells. We consider ATP7B c.3207C>A to be pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002072934.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: The missense variant p.H1069Q in ATP7B (NM_000053.3) has been previously reported in affected individuals and is the most common variant in Central and Eastern European … (more) The missense variant p.H1069Q in ATP7B (NM_000053.3) has been previously reported in affected individuals and is the most common variant in Central and Eastern European countries. It is submitted to the Clinvar database as Pathogenic. The p.H1069Q variant is observed in 54/10,066 (0.5365%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exome. The p.H1069Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 1069 of ATP7B is conserved in all mammalian species. The nucleotide c.3207 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Elevated circulating hepatic transaminase concentration (present) , Increased circulating ferritin concentration (present) , Tapered finger (present) , Mitochondrial depletion (present)
Pathogenic (Aug 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767518.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous missense variant, NM_000053.3(ATP7B):c.3207C>A, has been identified in exon 14 of 21 of the ATP7B gene. The variant is predicted to result in a … (more) A heterozygous missense variant, NM_000053.3(ATP7B):c.3207C>A, has been identified in exon 14 of 21 of the ATP7B gene. The variant is predicted to result in a minor amino acid change from histidine to glutamine at position 1069 of the protein (NP_000044.2(ATP7B):p.(His1069Gln)). The histidine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the ATP loop domain (Wilson Disease Mutation Database). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.1% (286 heterozygotes, 0 homozygotes). This variant has been previously described as pathogenic, and is one of the most common pathogenic alleles causing Wilsons disease (Kluska, A., et al. (2019), ClinVar, Wilson Disease Database). Additionally, functional studies of mutant protein disrupts intracelleular copper balance and reduced protein stability (Huster D. et al. (2003), Rodriguez-Granillo, A., et al. (2008)). An alternative change at the same codon to asparagine has also been reported in a patient with Wilson's disease (Zali, N., et al. (2011)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Pathogenic (Feb 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611174.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022
Pathogenic (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920292.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: ATP7B NM_000053.3 exon 14 p.His1069Gln (c.3207C>A): This variant is one of the most common pathogenic variants in the ATP7B gene and has been reported in … (more) ATP7B NM_000053.3 exon 14 p.His1069Gln (c.3207C>A): This variant is one of the most common pathogenic variants in the ATP7B gene and has been reported in both the homozygous and compound heterozygous state in several individuals with Wilson disease (Tanzi 1993 PMID: 8298641, Duc 1998 PMID:9887381, Firneisz 2002 PMID:11857545). This variant is present in 0.1% (196/128580) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-52518281-G-T?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:3848). Evolutionary conservation and computational predictive tools support that this variant will impact the protein. In vivo and In vitro functional studies suggest that this variant reduces ATP binding and is retained in the endoplasmic reticulum (Morgan 2004 PMID:15205462, Mercer 2017 PMID:28119449, Parisi 2018 PMID:29674751). In summary, this variant is classified as pathogenic. (less)
Pathogenic (Mar 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004361971.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (41) PubMed: 7626145‚ 8298641‚ 9214248‚ 9352458‚ 9654149‚ 9724794‚ 9887381‚ 10051024‚ 10406672‚ 10544227‚ 11857545‚ 12557139‚ 15967699‚ 16207219‚ 17717039‚ 18311837‚ 18692069‚ 19306278‚ 19937698‚ 21398519‚ 22221592‚ 22240481‚ 22286624‚ 22692182‚ 22720308‚ 22730635‚ 23430908‚ 24253677‚ 24897373‚ 24909901‚ 26286547‚ 28119449‚ 28776642‚ 29674751‚ 30026388‚ 30609409‚ 31708252‚ 32043565‚ 32270360‚ 32532207‚ 33098801 Comment: This missense variant replaces histidine with glutamine at codon 1069 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces histidine with glutamine at codon 1069 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). Functional studies have shown that this variant results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388). This variant has been reported in numerous homozygous and compound heterozygous individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9214248, 9352458, 9887381, 10051024, 10406672, 10544227, 11857545, 12557139, 15967699, 16207219, 18311837, 19306278, 22286624, 22221592, 22720308, 22730635, 23430908, 24897373, 26286547, 28776642, 30609409, 31708252, 32043565, 32270360, 32532207, 33098801) and has been shown to segregate with disease in family studies (PMID: 24897373, 31708252, 32043565, 32532207). Homozygosity for this variant is the most common cause of Wilson disease among patients of European ancestry (PMID: 7626145, 9724794, 9887381). This variant has been identified in 286/280766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Aug 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602583.8 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The ATP7B c.3207C>A; p.His1069Gln variant (rs76151636), also known as His714Gln, has been reported in the homozygous and compound heterozygous state in numerous individuals diagnosed with … (more) The ATP7B c.3207C>A; p.His1069Gln variant (rs76151636), also known as His714Gln, has been reported in the homozygous and compound heterozygous state in numerous individuals diagnosed with Wilson disease (Cocos 2014, Duc 1998, Tanzi 1993). Functional studies indicate that the variant protein has altered subcellular localization (Payne 1998, van den Berghe 2009), reduced affinity to ATP (Morgan 2004, Rodriguez-Granillo 2008) and reduced half-life (Payne 1998). Cells expressing the variant protein show reduced viability when exposed to increased levels of copper (Payne 1998). This variant is reported in ClinVar (Variation ID: 3848) and is found in the general population with an overall allele frequency of 0.10% (286/280766 alleles) in the Genome Aggregation Database. The histidine at codon 1069 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.909). Based on available information, this variant is considered to be pathogenic. References: Cocos R et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One. 2014 9(6):e98520. PMID: 24897373. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 6(6):616-23. PMID: 9887381. Morgan C 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 279(35):36363-71. PMID: 15205462. Payne AS et al. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci U S A. 1998 95(18):10854-9. PMID: 9724794. Rodriguez-Granillo A et al. Stability and ATP binding of the nucleotide-binding domain of the Wilson disease protein: effect of the common H1069Q mutation. J Mol Biol. 2008 383(5):1097-111. PMID: 18692069. Tanzi R et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 5(4):344-50. PMID: 8298641. van den Berghe P et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology. 2009 50(6):1783-95. PMID: 19937698. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000626851.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (12) PubMed: 28492532‚ 8298641‚ 9887381‚ 18311837‚ 22221592‚ 22286624‚ 22720308‚ 24897373‚ 9724794‚ 19937698‚ 22240481‚ 24909901 Comment: This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1069 of the ATP7B protein (p.His1069Gln). … (more) This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1069 of the ATP7B protein (p.His1069Gln). This variant is present in population databases (rs76151636, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease. This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe and has been mainly associated in the homozygous state with a late onset course of the disease. (PMID: 8298641, 9887381, 18311837, 22221592, 22286624, 22720308, 24897373). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3848). 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: 9724794, 19937698, 22240481, 24909901). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052016.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2024	Publications: PubMed (6) PubMed: 17717039‚ 10544227‚ 11690702‚ 15205462‚ 24897373‚ 21334398 Comment: Variant summary: ATP7B c.3207C>A (p.His1069Gln) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein … (more) Variant summary: ATP7B c.3207C>A (p.His1069Gln) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 249392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00092 vs 0.0054), allowing no conclusion about variant significance. c.3207C>A has been reported in the literature in numerous individuals affected with Wilson Disease (e.g., Cocos_2014, Gromadzka_2010, Loudianos_1999, Caca_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal nucleotide binding activity (e.g., Morgan_2004). The following publications have been ascertained in the context of this evaluation (PMID: 17717039, 10544227, 11690702, 15205462, 24897373, 21334398). ClinVar contains an entry for this variant (Variation ID: 3848). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 06, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002610410.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 8298641‚ 9887381‚ 15205462‚ 15523622‚ 18692069‚ 21398519‚ 23430908 Comment: The c.3207C>A (p.H1069Q) alteration is located in exon 14 (coding exon 14) of the ATP7B gene. This alteration results from a C to A substitution … (more) The c.3207C>A (p.H1069Q) alteration is located in exon 14 (coding exon 14) of the ATP7B gene. This alteration results from a C to A substitution at nucleotide position 3207, causing the histidine (H) at amino acid position 1069 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.1% (286/280766) total alleles studied. The highest observed frequency was 0.53% (55/10356) of Ashkenazi Jewish alleles. The p.H1069Q alteration is the most common mutation found in Wilson disease. Thirteen homozygous individuals with Wilson disease were observed to present at a later age, have a high occurrence of hepatic disease, and display neurological symptoms more often than compound heterozygotes with a different mutation (Panagiotakaki, 2004). Another study showed that when compared to individuals with mutations other than p.H1069Q, those with p.H1069Q were less likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and more likely to have a neurologic phenotype (Usta, 2012). Another study of 7 homozygotes displayed a larger degree of phenotypic variability, although 4 individuals presented with neurological disease (Duc, 1998). This amino acid position is highly conserved in available vertebrate species. Based on several functional studies, this mutation affects ATP binding, protein dynamics, and chemical and thermal stabilities relative to wild type (Rodriguez-Granillo, 2008; Dmitriev, 2011; Morgan, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jun 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715041.3 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Publications: Bookshelf: NBK1512 Bookshelf: NBK1512 Number of individuals with the variant: 44
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Wilson disease Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052021.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001163729.2 First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024
Pathogenic (May 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429292.2 First in ClinVar: Aug 17, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PM3_VSTR,PM5_STR,PS3_MOD,PP3 Clinical Features: Abnormal liver morphology (present) Sex: female
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247795.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: ATP7B: PM3:Very Strong, PM1, PM2, PM5, PS3:Moderate Number of individuals with the variant: 46
Pathogenic (Nov 01, 2005)	no assertion criteria provided Method: literature only	WILSON DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024218.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (6) PubMed: 7626145‚ 8533760‚ 9724794‚ 9887381‚ 11857545‚ 16207219 Comment on evidence: In a study of 58 patients with Wilson disease (277900), Thomas et al. (1995) found that 28% had a mutation that they referred to as … (more) In a study of 58 patients with Wilson disease (277900), Thomas et al. (1995) found that 28% had a mutation that they referred to as H1070Q (HIS1070GLN), located in the loop motif and disrupting ATP binding. The patients (19 in number) were of Eastern European, German, French, and British extraction. This mutation was homozygous in 6 families; there was variation in age of onset within these families and an equal number of hepatic and neurologic cases. The average age of onset of symptoms in patients homozygous for the mutation was 16.8 years. The same mutation was found in heterozygous state (compound heterozygotes) in 9 families with a total of 11 patients, with an average age of onset of 17.3 years. Figus et al. (1995) concluded that this mutation is probably the most common molecular defect of the WND gene and may have arisen as a single and very ancient mutation event. Payne et al. (1998) stated that the H1069Q mutation represents up to 37% of Wilson disease alleles in patients of Eastern European descent and studied the function of the ATP7B protein by expressing wildtype and mutant ATP7B cDNAs in a Menkes copper transporter-deficient 'mottled' fibroblast cell line defective in copper export. Expression of the wildtype cDNA demonstrated trans-Golgi network localization and copper-dependent trafficking of the ATP7B protein identical to previous observations for the endogenously expressed protein in hepatocytes. Furthermore, expression of the ATP7B cDNA rescued the 'mottled' phenotype as evidenced by a reduction in copper accumulation and restoration of cell liability. In contrast, expression of an H1069Q mutant ATP7B cDNA did not rescue the 'mottled' phenotype, and immunofluorescence studies showed that this mutant ATP7B protein was localized in the endoplasmic reticulum. Pulse-chase analysis demonstrated a 5-fold decrease in the half-life of the H1069Q mutant as compared with the wildtype protein. Maintenance of these transfected cell lines at 28 degrees C resulted in localization of the H1069Q protein in the trans-Golgi network, suggesting that a temperature-sensitive defect in protein folding followed by degradation constitutes the molecular basis of Wilson disease in patients harboring the H1069Q mutation. The results provided compelling evidence that the ATP7B protein can functionally substitute for the Menkes disease protein, ATP7A, supporting the concept that these proteins use common biochemical mechanisms to effect cellular copper homeostasis. Ha-Hao et al. (1998) found this mutation in 42% of WND chromosomes in a series of 33 German cases of Wilson disease. Haplotype C was highly predictive for this mutation. Patients homozygous for the mutation showed almost a complete range of clinical presentations; in this series, the his1069-to-gln mutation was not associated with a late neurologic presentation. Firneisz et al. (2002) found the H1069Q mutation in 27 Hungarian patients with Wilson disease, 64.3% of their series. In 9 of the 27 patients, H1069Q was homozygous. They found that H1069Q-positive patients from various European countries had the same haplotype pattern. Thus the H1069Q mutation appears to have originated from a single founder, at least in Europe. Among 80 unrelated Bulgarian families with Wilson disease, Todorov et al. (2005) found that the H1069Q mutation was the most common mutation with an allelic frequency of 58.75%. All 15 families of the Roma ethnic group had the H1069Q mutation, consistent with the Roma being a genetic isolate with frequent consanguinity and endogamy. (less)
Pathogenic (Apr 11, 2018)	no assertion criteria provided Method: case-control	Wilson Disease Affected status: yes Allele origin: unknown	Genomics And Bioinformatics Analysis Resource, Columbia University Accession: SCV000778805.2 First in ClinVar: May 26, 2018 Last updated: Sep 23, 2023	Testing laboratory: HNL Genomics Connective Tissue Gene Tests Date variant was reported to submitter: 2018-04-11
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455593.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Wilson disease Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142439.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: NM_000053.3:c.3207C>A in the ATP7B gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.His1069Gln had … (more) NM_000053.3:c.3207C>A in the ATP7B gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.His1069Gln had a very low activity comprared to wildtype (PMID: 22240481), resulted in reduced ATP7B protein expression (PMID: 19937698), and caused subcellular mislocalization (PMID: 24909901). This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe, and was identified in mutiple compound heterozygous or homozygous, such as H1069Q/M769H (PMID: 24897373), H1069Q/H1069Q (PMID: 22720308), H1069Q/H1069Q (PMID: 22221592). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. (less)
not provided (-)	no classification provided Method: phenotyping only	Wilson disease Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV001423265.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. 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. (less) Clinical Features: Hyperthyroidism (present) , Depressivity (present) , Gingivitis (present) Indication for testing: Carrier Screening Age: 30-39 years Sex: female Testing laboratory: Myriad Genetic Laboratories, Inc.,Myriad Genetic Laboratories, Inc. Date variant was reported to submitter: 2019-06-04 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Wilson disease Affected status: yes Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749845.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Pathogenic and reported on 03-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 03-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormality of thrombocytes (present) , Pregnancy history (present) Indication for testing: Diagnostic Age: 30-39 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-03-02 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Wilson disease Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086653.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 8298641‚ 20301685 BookShelf: NBK1512 BookShelf: NBK1512
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Comment:

The p.His1069Gln variant in ATP7B has been reported in numerous homozygous and compound heterozygous individuals with Wilson disease and is the most common variant identified in European patients (Tanzi 1993, Duc 1999, Ivanova-Smolenskaya 1999, Caca 2001, Cocos 2014). This variant has also been reported by clinical laboratories in ClinVar (Variation ID#3848) and been identified in 0.5% (53/10148) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is consistent with the known carrier frequency of Wilson disease. In vitro functional studies provide some evidence that the p.His1069Gln variant may result in reduced ATP7B protein expression (van den Berghe 2009) and computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease based upon its common biallelic occurrence in patients with this disease and functional evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting.

Comment:

NM_000053.3(ATP7B):c.3207C>A(H1069Q) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9352458, 9887381, 11857545, and 7626145. Classification of NM_000053.3(ATP7B):c.3207C>A(H1069Q) 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.

Comment:

The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.102%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.93). The the same nucleotide change resulting in the the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003848/PMID:8298641/3billion dataset). Different missense changes at the the same codon (p.His1069Arg, p.His1069Asn, p.His1069Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001069926/PMID: 21645214, 22308153). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This missense variant replaces histidine with glutamine at codon 1069 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). Functional studies have shown that this variant results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388). This variant has been reported in numerous homozygous and compound heterozygous individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9214248, 9352458, 9887381, 10051024, 10406672, 10544227, 11857545, 12557139, 15967699, 16207219, 18311837, 19306278, 22286624, 22221592, 22720308, 22730635, 23430908, 24897373, 26286547, 28776642, 30609409, 31708252, 32043565, 32270360, 32532207, 33098801) and has been shown to segregate with disease in family studies (PMID: 24897373, 31708252, 32043565, 32532207). Homozygosity for this variant is the most common cause of Wilson disease among patients of European ancestry (PMID: 7626145, 9724794, 9887381). This variant has been identified in 286/280766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

Published functional studies show the H1069Q variant has significantly reduced ATP binding affinity and reduced protein stability, leading to impaired copper transport (Dmitriev et al., 2011; Morgan et al., 2004; Rodriguez-Granillo et al., 2008; Chesi et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22692182, 25333069, 24897373, 22730635, 22240481, 28392828, 27641668, 28119449, 28776642, 30609409, 31028847, 28602929, 23430908, 19306278, 22286624, 30232804, 15024742, 23982005, 24253677, 24909901, 9887381, 9654149, 18692069, 22221592, 8298641, 11857545, 15967699, 27122662, 26660341, 18311837, 10406672, 19937698, 26286547, 16567646, 28717664, 23159873, 22763723, 18855987, 9724794, 29674751, 15205462, 21398519, 31708252, 31664448, 31980526, 32043565, 32532207)

Comment:

ATP7B c.3207C>A has been identified in the homozygous or compound heterozygous state in many individuals with Wilson disease. It is the most common pathogenic ATP7B variant associated with Wilson disease in populations of European origin. This variant (rs76151636) is present in a large population dataset (gnomAD: 286/280766 total alleles; 0.1019%; no homozygotes) and has been reported in ClinVar. Functional studies demonstrate that this substitution results in mislocalization and increased degradation of the ATP7B protein in cells. We consider ATP7B c.3207C>A to be pathogenic.

Comment:

The missense variant p.H1069Q in ATP7B (NM_000053.3) has been previously reported in affected individuals and is the most common variant in Central and Eastern European countries. It is submitted to the Clinvar database as Pathogenic. The p.H1069Q variant is observed in 54/10,066 (0.5365%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exome. The p.H1069Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 1069 of ATP7B is conserved in all mammalian species. The nucleotide c.3207 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

A heterozygous missense variant, NM_000053.3(ATP7B):c.3207C>A, has been identified in exon 14 of 21 of the ATP7B gene. The variant is predicted to result in a minor amino acid change from histidine to glutamine at position 1069 of the protein (NP_000044.2(ATP7B):p.(His1069Gln)). The histidine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the ATP loop domain (Wilson Disease Mutation Database). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.1% (286 heterozygotes, 0 homozygotes). This variant has been previously described as pathogenic, and is one of the most common pathogenic alleles causing Wilsons disease (Kluska, A., et al. (2019), ClinVar, Wilson Disease Database). Additionally, functional studies of mutant protein disrupts intracelleular copper balance and reduced protein stability (Huster D. et al. (2003), Rodriguez-Granillo, A., et al. (2008)). An alternative change at the same codon to asparagine has also been reported in a patient with Wilson's disease (Zali, N., et al. (2011)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

ATP7B NM_000053.3 exon 14 p.His1069Gln (c.3207C>A): This variant is one of the most common pathogenic variants in the ATP7B gene and has been reported in both the homozygous and compound heterozygous state in several individuals with Wilson disease (Tanzi 1993 PMID: 8298641, Duc 1998 PMID:9887381, Firneisz 2002 PMID:11857545). This variant is present in 0.1% (196/128580) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-52518281-G-T?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:3848). Evolutionary conservation and computational predictive tools support that this variant will impact the protein. In vivo and In vitro functional studies suggest that this variant reduces ATP binding and is retained in the endoplasmic reticulum (Morgan 2004 PMID:15205462, Mercer 2017 PMID:28119449, Parisi 2018 PMID:29674751). In summary, this variant is classified as pathogenic.

Comment:

The ATP7B c.3207C>A; p.His1069Gln variant (rs76151636), also known as His714Gln, has been reported in the homozygous and compound heterozygous state in numerous individuals diagnosed with Wilson disease (Cocos 2014, Duc 1998, Tanzi 1993). Functional studies indicate that the variant protein has altered subcellular localization (Payne 1998, van den Berghe 2009), reduced affinity to ATP (Morgan 2004, Rodriguez-Granillo 2008) and reduced half-life (Payne 1998). Cells expressing the variant protein show reduced viability when exposed to increased levels of copper (Payne 1998). This variant is reported in ClinVar (Variation ID: 3848) and is found in the general population with an overall allele frequency of 0.10% (286/280766 alleles) in the Genome Aggregation Database. The histidine at codon 1069 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.909). Based on available information, this variant is considered to be pathogenic. References: Cocos R et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One. 2014 9(6):e98520. PMID: 24897373. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 6(6):616-23. PMID: 9887381. Morgan C 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 279(35):36363-71. PMID: 15205462. Payne AS et al. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci U S A. 1998 95(18):10854-9. PMID: 9724794. Rodriguez-Granillo A et al. Stability and ATP binding of the nucleotide-binding domain of the Wilson disease protein: effect of the common H1069Q mutation. J Mol Biol. 2008 383(5):1097-111. PMID: 18692069. Tanzi R et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 5(4):344-50. PMID: 8298641. van den Berghe P et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology. 2009 50(6):1783-95. PMID: 19937698.

Comment:

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1069 of the ATP7B protein (p.His1069Gln). This variant is present in population databases (rs76151636, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease. This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe and has been mainly associated in the homozygous state with a late onset course of the disease. (PMID: 8298641, 9887381, 18311837, 22221592, 22286624, 22720308, 24897373). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3848). 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: 9724794, 19937698, 22240481, 24909901). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: ATP7B c.3207C>A (p.His1069Gln) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 249392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00092 vs 0.0054), allowing no conclusion about variant significance. c.3207C>A has been reported in the literature in numerous individuals affected with Wilson Disease (e.g., Cocos_2014, Gromadzka_2010, Loudianos_1999, Caca_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal nucleotide binding activity (e.g., Morgan_2004). The following publications have been ascertained in the context of this evaluation (PMID: 17717039, 10544227, 11690702, 15205462, 24897373, 21334398). ClinVar contains an entry for this variant (Variation ID: 3848). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The c.3207C>A (p.H1069Q) alteration is located in exon 14 (coding exon 14) of the ATP7B gene. This alteration results from a C to A substitution at nucleotide position 3207, causing the histidine (H) at amino acid position 1069 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.1% (286/280766) total alleles studied. The highest observed frequency was 0.53% (55/10356) of Ashkenazi Jewish alleles. The p.H1069Q alteration is the most common mutation found in Wilson disease. Thirteen homozygous individuals with Wilson disease were observed to present at a later age, have a high occurrence of hepatic disease, and display neurological symptoms more often than compound heterozygotes with a different mutation (Panagiotakaki, 2004). Another study showed that when compared to individuals with mutations other than p.H1069Q, those with p.H1069Q were less likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and more likely to have a neurologic phenotype (Usta, 2012). Another study of 7 homozygotes displayed a larger degree of phenotypic variability, although 4 individuals presented with neurological disease (Duc, 1998). This amino acid position is highly conserved in available vertebrate species. Based on several functional studies, this mutation affects ATP binding, protein dynamics, and chemical and thermal stabilities relative to wild type (Rodriguez-Granillo, 2008; Dmitriev, 2011; Morgan, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

NM_000053.3:c.3207C>A in the ATP7B gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.His1069Gln had a very low activity comprared to wildtype (PMID: 22240481), resulted in reduced ATP7B protein expression (PMID: 19937698), and caused subcellular mislocalization (PMID: 24909901). This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe, and was identified in mutiple compound heterozygous or homozygous, such as H1069Q/M769H (PMID: 24897373), H1069Q/H1069Q (PMID: 22720308), H1069Q/H1069Q (PMID: 22221592). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3.

Comment:

Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. 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.

Comment:

Variant interpreted as Pathogenic and reported on 03-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Wilson Disease.	Adam MP	-	2023	PMID: 20301685
Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss.	Zhao C	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33100332
Monogenic variants in dystonia: an exome-wide sequencing study.	Zech M	The Lancet. Neurology	2020	PMID: 33098801
Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype.	Sapuppo A	BMC medical genetics	2020	PMID: 32532207
Transcranial sonography changes in heterozygotic carriers of the ATP7B gene.	Skowronska M	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2020	PMID: 32270360
Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain.	Sánchez-Monteagudo A	Clinical genetics	2020	PMID: 32043565
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation.	Balashova MS	Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)	2020	PMID: 31708252
Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation.	McCreary D	JAMA network open	2019	PMID: 31664448
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease.	Wattacheril J	Cold Spring Harbor molecular case studies	2018	PMID: 30026388
Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells.	Parisi S	Scientific reports	2018	PMID: 29674751
Diagnosis of monogenic liver diseases in childhood by next-generation sequencing.	Stalke A	Clinical genetics	2018	PMID: 28776642
Hereditary Multiple Cerebral Cavernous Malformations Associated with Wilson Disease and Multiple Lipomatosis.	Belousova OB	World neurosurgery	2017	PMID: 28602929
In Vivo Modeling of the Pathogenic Effect of Copper Transporter Mutations That Cause Menkes and Wilson Diseases, Motor Neuropathy, and Susceptibility to Alzheimer's Disease.	Mercer SW	The Journal of biological chemistry	2017	PMID: 28119449
Wilson disease: a most unusual patient.	Walshe JM	QJM : monthly journal of the Association of Physicians	2016	PMID: 26286547
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.	Polishchuk EV	Developmental cell	2014	PMID: 24909901
Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity.	Cocoş R	PloS one	2014	PMID: 24897373
In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure.	Squitti R	Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine	2014	PMID: 24253677
Homozygosity for Non-H1069Q Missense Mutations in ATP7B Gene and Early Severe Liver Disease: Report of Two Families and a Meta-analysis.	Usta J	JIMD reports	2012	PMID: 23430908
Good response with zinc acetate monotherapy in an adolescent affected by severe Wilson disease.	Marazzi MG	La Pediatria medica e chirurgica : Medical and surgical pediatrics	2012	PMID: 22730635
The His1069Gln mutation in the ATP7B gene in Romanian patients with Wilson's disease referred to a tertiary gastroenterology center.	Iacob R	Journal of gastrointestinal and liver diseases : JGLD	2012	PMID: 22720308
A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism.	Schushan M	Metallomics : integrated biometal science	2012	PMID: 22692182
Diverse functional properties of Wilson disease ATP7B variants.	Huster D	Gastroenterology	2012	PMID: 22240481
Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation.	Litwin T	Parkinsonism & related disorders	2012	PMID: 22221592
Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease.	Zali N	Hepatitis monthly	2011	PMID: 22308153
Acute Gallbladder Hydrops and Arthritis: unusual initial manifestations of Wilson's Disease (WD): Case Report.	Gucev ZS	Prilozi	2011	PMID: 22286624
Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.	Lee BH	Liver international : official journal of the International Association for the Study of the Liver	2011	PMID: 21645214
Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B.	Dmitriev OY	The Journal of biological chemistry	2011	PMID: 21398519
Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.	Gromadzka G	Journal of hepatology	2011	PMID: 21334398
Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin.	van den Berghe PV	Hepatology (Baltimore, Md.)	2009	PMID: 19937698
Monozygotic female twins discordant for phenotype of Wilson's disease.	Członkowska A	Movement disorders : official journal of the Movement Disorder Society	2009	PMID: 19306278
Stability and ATP binding of the nucleotide-binding domain of the Wilson disease protein: effect of the common H1069Q mutation.	Rodriguez-Granillo A	Journal of molecular biology	2008	PMID: 18692069
Late onset Wilson's disease: therapeutic implications.	Członkowska A	Movement disorders : official journal of the Movement Disorder Society	2008	PMID: 18311837
Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes.	de Bie P	Journal of medical genetics	2007	PMID: 17717039
Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population.	Todorov T	Clinical genetics	2005	PMID: 16207219
Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease.	Vrabelova S	Molecular genetics and metabolism	2005	PMID: 15967699
Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B).	Panagiotakaki E	American journal of medical genetics. Part A	2004	PMID: 15523622
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.	Morgan CT	The Journal of biological chemistry	2004	PMID: 15205462
Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines.	Huster D	Gastroenterology	2003	PMID: 12557139
Common mutations of ATP7B in Wilson disease patients from Hungary.	Firneisz G	American journal of medical genetics	2002	PMID: 11857545
High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.	Caca K	Journal of hepatology	2001	PMID: 11690702
Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.	Loudianos G	Journal of medical genetics	1999	PMID: 10544227
Detection of a rare Wilson disease mutation associated with arylsulfatase A pseudodeficiency.	Battisti C	American journal of medical genetics	1999	PMID: 10406672
The His1069Gln mutation in the ATP7B gene in Russian patients with Wilson disease.	Ivanova-Smolenskaya IA	Journal of medical genetics	1999	PMID: 10051024
His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype.	Duc HH	European journal of human genetics : EJHG	1998	PMID: 9887381
Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation.	Payne AS	Proceedings of the National Academy of Sciences of the United States of America	1998	PMID: 9724794
Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae.	Iida M	FEBS letters	1998	PMID: 9654149
Very high frequency of the His1069Gln mutation in Polish Wilson disease patients.	Czlonkowska A	Journal of neurology	1997	PMID: 9352458
Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.	Maier-Dobersberger T	Annals of internal medicine	1997	PMID: 9214248
Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.	Figus A	American journal of human genetics	1995	PMID: 8533760
The Wilson disease gene: spectrum of mutations and their consequences.	Thomas GR	Nature genetics	1995	PMID: 7626145
The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.	Tanzi RE	Nature genetics	1993	PMID: 8298641
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B	-	-	-	-
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Text-mined citations for rs76151636 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln)

Variant Details

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Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs76151636 ...