NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln) AND Wilson disease

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: May 2, 2024
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:: RCV000004064.26

Allele description [Variation Report for NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln)]

NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln)

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.2906G>A (p.Arg969Gln)

HGVS:

NC_000013.11:g.51946438C>T
NG_008806.1:g.70057G>A
NM_000053.4:c.2906G>AMANE SELECT
NM_001005918.3:c.2285G>A
NM_001243182.2:c.2573G>A
NM_001330578.2:c.2672G>A
NM_001330579.2:c.2654G>A
NP_000044.2:p.Arg969Gln
NP_001005918.1:p.Arg762Gln
NP_001230111.1:p.Arg858Gln
NP_001317507.1:p.Arg891Gln
NP_001317508.1:p.Arg885Gln
NC_000013.10:g.52520574C>T
NM_000053.3:c.2906G>A
P35670:p.Arg969Gln

Protein change:

R762Q; ARG969GLN

Links:

UniProtKB: P35670#VAR_000747; OMIM: 606882.0018; dbSNP: rs121907996

NCBI 1000 Genomes Browser:

rs121907996

Molecular consequence:

NM_000053.4:c.2906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2285G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2573G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2672G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2654G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024230	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8533760, 15523622
SCV000678091	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Jan 2, 2014)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15523622, 8533760, 22240481, 16791614 Citation Link,
SCV000916622	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15523622, 9801873, 10544227, 22240481, 22692182, 8533760 Citation Link,
SCV001229234	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 23, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8533760, 9801873, 17325640, 20517649, 22308153, 26819605, 22240481, 22692182, 28492532
SCV001459715	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001810283	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002564592	Arcensus	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002600204	Credence Genomics	no assertion criteria provided	Pathogenic (Dec 20, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8533760, 26819605
SCV002780476	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 11, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004032256	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216257	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 11, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004238450	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847827	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9801873, 22240481, 8533760, 24517292, 26215059, 16791614, 22692182, 15523622, 10544227, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	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
not provided	germline	yes	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
South Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Screening for mutations in ATP7B gene using conformation-sensitive gel electrophoresis in a family with Wilson's disease.

Sundaresan S, Eapen CE, Shaji RV, Chandy M, Kurian G, Chandy G.

Med Sci Monit. 2007 Mar;13(3):CS38-40.

PubMed [citation]

PMID:: 17325640

Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease.

Weiss KH, Runz H, Noe B, Gotthardt DN, Merle U, Ferenci P, Stremmel W, Füllekrug J.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40. doi: 10.1007/s10545-010-9123-5. Epub 2010 Jun 2.

PubMed [citation]

PMID:: 20517649

See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000024230.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In patients with Wilson disease (WND; 277900), Figus et al. (1995) identified a 2906G-A transition in exon 13 of the ATP7B gene, resulting in an arg969-to-gln (R969Q) substitution. Panagiotakaki et al. (2004) found this mutation in 12% of chromosomes from 93 Greek patients with Wilson disease.

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

From Counsyl, SCV000678091.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916622.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: Variant summary: The ATP7B c.2906G>A (p.Arg969Gln) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type_ATPase_Cu-like domain and 3/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional studies, where R969Q was shown to markedly affect copper transport and lead to hyperphosphorylation (Huster, 2012). This variant was found in 10/277242 control chromosomes at a frequency of 0.000036, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals with clinically and biochemically confirmed Wilsons disease (WD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001229234.5

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 969 of the ATP7B protein (p.Arg969Gln). This variant is present in population databases (rs121907996, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8533760, 9801873, 17325640, 20517649, 22308153, 26819605). This variant is also known as p.Arg970Gln. ClinVar contains an entry for this variant (Variation ID: 3860). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.

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

From Natera, Inc., SCV001459715.1

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

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

From Genome-Nilou Lab, SCV001810283.1

#	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 Arcensus, SCV002564592.1

#	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 Credence Genomics, SCV002600204.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

Reviewed for liver cirrhosis and evaluated for liver transplantation

Description

The specific mutation is seen to affect the ATP7B in certain populations and in turn lowering ceruloplasmin levels https://www.nature.com/articles/s41598-021-87000-9

#	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		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002780476.1

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

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004032256.3

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

Description

Criteria applied: PS3, PM5, PM3_VSTR,PM2_SUP,PP3,PP4

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

From Baylor Genetics, SCV004216257.2

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

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

From Revvity Omics, Revvity, SCV004238450.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847827.1

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

Description

The p.Arg969Gln variant in ATP7B has been reported in >20 probands with Wilson disease, including at least 13 homozygotes and 14 compound heterozygotes (Ferenci 2014), and has been reported in ClinVar (Variation ID 3860). It has also been identified in 3/30600 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson Disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Supporting, PP3.

#	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: Oct 20, 2024

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