NM_000053.4(ATP7B):c.2293G>A (p.Asp765Asn) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Dec 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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

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

Record status:: current
Accession:: RCV000004059.24

Allele description [Variation Report for NM_000053.4(ATP7B):c.2293G>A (p.Asp765Asn)]

NM_000053.4(ATP7B):c.2293G>A (p.Asp765Asn)

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.2293G>A (p.Asp765Asn)

HGVS:

NC_000013.11:g.51958373C>T
NG_008806.1:g.58122G>A
NM_000053.4:c.2293G>AMANE SELECT
NM_001005918.3:c.1870-766G>A
NM_001243182.2:c.1960G>A
NM_001330578.2:c.2122-766G>A
NM_001330579.2:c.2041G>A
NP_000044.2:p.Asp765Asn
NP_001230111.1:p.Asp654Asn
NP_001317508.1:p.Asp681Asn
NC_000013.10:g.52532509C>T
NM_000053.3:c.2293G>A
P35670:p.Asp765Asn

Protein change:

D654N; ASP765ASN

Links:

UniProtKB: P35670#VAR_000724; OMIM: 606882.0012; dbSNP: rs28942075

NCBI 1000 Genomes Browser:

rs28942075

Molecular consequence:

NM_001005918.3:c.1870-766G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001330578.2:c.2122-766G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000053.4:c.2293G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.1960G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2041G>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

Recent activity

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glutamate decarboxylase, putative [Aspergillus clavatus NRRL 1]
glutamate decarboxylase, putative [Aspergillus clavatus NRRL 1]
gi|121705704|ref|XP_001271115.1|

Protein
ParB-like nuclease domain protein [Streptomyces phage Sushi23]
ParB-like nuclease domain protein [Streptomyces phage Sushi23]
gi|1227559919|gb|ASR76443.1|

Protein
hypothetical protein SEA_TACHEZ_64 [Mycobacterium phage Tachez]
hypothetical protein SEA_TACHEZ_64 [Mycobacterium phage Tachez]
gi|1233033637|gb|ASR87670.1|

Protein
putative WHSC1 protein [Homo sapiens]
putative WHSC1 protein [Homo sapiens]
gi|4521955|gb|AAD21771.1|

Protein
Rattus norvegicus aldehyde dehydrogenase (ALDH) mRNA, complete cds
Rattus norvegicus aldehyde dehydrogenase (ALDH) mRNA, complete cds
gi|2183216|gb|AF001898.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024225	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1995)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000192324	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000486748	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Aug 1, 2016)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12557139, 23518715, 9482578, 15024742, 21682854, 23333878, 20517649 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001977336	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002247011	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15024742, 20517649, 9837819, 10942420, 23843956, 30384382, 28492532
SCV002511694	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9482578, 31708252 Citation Link,
SCV004216340	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004845550	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9837819, 10942420, 12557139, 15024742, 16283883, 20517649, 23333878, 23518715, 31708252, 33783954, 36588756, 25741868
SCV004847857	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9837819, 17717039, 8533760, 10942420, 15024742, 18483695, 16283883, 9482578, 11690702, 10502777, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients.

Abdel Ghaffar TY, Elsayed SM, Elnaghy S, Shadeed A, Elsobky ES, Schmidt H.

BMC Pediatr. 2011 Jun 17;11:56. doi: 10.1186/1471-2431-11-56.

PubMed [citation]

PMID:: 21682854
PMCID:: PMC3132721

Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease.

Gu S, Yang H, Qi Y, Deng X, Zhang L, Guo Y, Huang Q, Li J, Shi X, Song Z, Deng H.

PLoS One. 2013 Jul 2;8(7):e66526. doi: 10.1371/journal.pone.0066526. Print 2013.

PubMed [citation]

PMID:: 23843956
PMCID:: PMC3699604

See all PubMed Citations (22)

Details of each submission

From OMIM, SCV000024225.3

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

Description

In patients with Wilson disease (WND; 277900), Figus et al. (1995) identified a GAC-to-AAC change in the ATP7B gene, resulting in an asp765-to-asn substitution.

#	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 Genetic Services Laboratory, University of Chicago, SCV000192324.2

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

From Counsyl, SCV000486748.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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

From Genome-Nilou Lab, SCV001977336.1

#	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 Invitae, SCV002247011.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 765 of the ATP7B protein (p.Asp765Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Wilson disease (PMID: 15024742, 20517649). This variant is also known as Asp766Asn. ClinVar contains an entry for this variant (Variation ID: 3855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 9837819, 10942420). This variant disrupts the p.Asp765 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23843956, 30384382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511694.1

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

Description

Variant summary: ATP7B c.2293G>A (p.Asp765Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249564 control chromosomes. c.2293G>A has been reported in the literature in multiple individuals affected with Wilson Disease. These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Baylor Genetics, SCV004216340.2

#	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 All of Us Research Program, National Institutes of Health, SCV004845550.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces aspartic acid with asparagine at codon 765 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). Experimental studies have shown partial loss of function and mislocalization in yeast and human cell assays (PMID: 9837819, 10942420, 12557139). This variant has been observed in individuals affected with autosomal recessive Wilson disease, including in the compound heterozygous state and homozygous state (PMID: 15024742, 16283883, 20517649, 23333878, 23518715, 31708252, 33783954, 36588756). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2294A>G (p.Asp765Gly), is considered to be disease-causing (ClinVar variation ID: 495406), suggesting that Asp at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847857.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Asp765Asn variant in ATP7B has been observed several individuals with Wilson disease, including at least 3 homozygotes, and segregated with disease in 2 affected relatives (Abdelghaffar 2008, Caca 2001, Curtis 1999, Deguti 2004, Figus 1995, Gromadzka 2005, Kalinsky 1998). It was absent from large population studies. The variant has also been reported in ClinVar (Variation ID 3855). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine its pathogenicity. In vitro functional studies in yeast and Chinese hamster ovary cells support an impact on protein function (Forbes 2000). Two additional variants involving this codon (p.Asp765Gly, p.Asp765His) have also been identified in individuals with Wilson disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM2, PM3, PP1_Moderate, PP3, PP4, PS3_Supporting.

#	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: Jun 17, 2024

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