NM_000053.4(ATP7B):c.1877G>C (p.Gly626Ala) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Feb 5, 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:: RCV000145253.33

Allele description [Variation Report for NM_000053.4(ATP7B):c.1877G>C (p.Gly626Ala)]

NM_000053.4(ATP7B):c.1877G>C (p.Gly626Ala)

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.1877G>C (p.Gly626Ala)

HGVS:

NC_000013.11:g.51961906C>G
NG_008806.1:g.54589G>C
NM_000053.4:c.1877G>CMANE SELECT
NM_001005918.3:c.1869+2966G>C
NM_001243182.2:c.1544G>C
NM_001330578.2:c.1877G>C
NM_001330579.2:c.1869+2966G>C
NP_000044.2:p.Gly626Ala
NP_001230111.1:p.Gly515Ala
NP_001317507.1:p.Gly626Ala
NC_000013.10:g.52536042C>G
NM_000053.2:c.1877G>C
NM_000053.3:c.1877G>C
P35670:p.Gly626Ala

Protein change:

G515A

Links:

UniProtKB: P35670#VAR_000712; dbSNP: rs587783299

NCBI 1000 Genomes Browser:

rs587783299

Molecular consequence:

NM_001005918.3:c.1869+2966G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001330579.2:c.1869+2966G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000053.4:c.1877G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.1544G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.1877G>C - 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
SCV000220323	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 15, 2014)	unknown	literature only	PubMed (9) [See all records that cite these PMIDs] 17919502, 8938442, 9311736, 18371106, 22240481, 8533760, 18203200, 16207219, 24706876 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000694406	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 24, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 8533760, 10544227, 17919502, 23518715, 22677543, 24706876, 22240481, 18203200, 26799313, 16207219, 33640437, 34400371 Citation Link,
SCV000832093	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 26799313, 17919502, 18203200, 22240481, 24706876, 28492532
SCV001522512	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001752711	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001977179	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002087860	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Feb 12, 2020)	germline	clinical testing
SCV003821404	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004846328	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 8533760, 8938442, 9311736, 10544227, 16207219, 18203200, 18371106, 22240481, 22677543, 22735241, 23518715, 24706876, 26799313, 33640437, 34400371, 36096368, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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, literature only
not provided	germline	unknown	22	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.

de Bie P, van de Sluis B, Burstein E, van de Berghe PV, Muller P, Berger R, Gitlin JD, Wijmenga C, Klomp LW.

Gastroenterology. 2007 Oct;133(4):1316-26. Epub 2007 Jul 25.

PubMed [citation]

PMID:: 17919502
PMCID:: PMC2857755

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (19)

Details of each submission

From Counsyl, SCV000220323.2

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

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694406.4

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

Description

Variant summary: ATP7B c.1877G>C (p.Gly626Ala) results in a non-conservative amino acid change located in the heavy metal-associated domain, copper ion-binding (IPR006122) 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 8.8e-05 in 249616 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.1877G>C has been reported in the literature on certain occasions in compound heterozygosity with other pathogenic variants (e.g. p.Gly1061Glu, p.His1069Gln), in multiple individuals affected with Wilson Disease (Bost_2012, Braiterman_2014, Coffey_2013, Figus_1995, Ljubic_2016, Loudianos_1999, Todorov_2005, Collins_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions about the variant effect. Specifically, one study demonstrated the variant to cause partial copper transport activity but normal phosphorylation activity (Huster_2012) while, other studies revealed normal copper transport and trafficking (Braiterman_2014, Hsi_2008). A separate study showed the variant protein retained its ability to interact with COMMD1 but at decreased efficiency (de Bie_2007); however, it is not conclusively established if and how this change could lead to disease. Therefore, these studies do not allow convincing conclusions about the variant effect. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic, n=6; pathogenic, n=1, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely 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 Invitae, SCV000832093.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 626 of the ATP7B protein (p.Gly626Ala). This variant is present in population databases (rs587783299, gnomAD 0.1%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 24706876, 26799313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly627Ala. ClinVar contains an entry for this variant (Variation ID: 157930). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 17919502, 18203200, 22240481, 24706876). 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 Baylor Genetics, SCV001522512.2

#	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 Fulgent Genetics, Fulgent Genetics, SCV001752711.1

#	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 Genome-Nilou Lab, SCV001977179.1

#	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 Natera, Inc., SCV002087860.1

#	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 Revvity Omics, Revvity, SCV003821404.2

#	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	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, SCV004846328.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant replaces glycine with alanine at codon 626 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 conflicting results on the impact of this variant on protein function (PMID: 18203200, 22240481, 24706876). One study showed this variant partially disrupted copper transport but maintained normal phosphorylation activity (PMID: 22240481), while two other studies showed normal copper transport and localization (PMID: 18203200, 24706876). This variant has been reported in many individuals affected with Wilson disease (PMID: 8533760, 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 23518715, 24706876, 26799313, 33640437, 34400371, 36096368). In a number of these individuals, this variant has been determined to be in the compound heterozygous state with another pathogenic variant (PMID: 23518715, 24706876, 26799313, 33640437). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 24/280910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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		22	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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