NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (15 submissions)
Last evaluated:: Apr 4, 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:: RCV000004055.34

Allele description [Variation Report for NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val)]

NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val)

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.2621C>T (p.Ala874Val)

HGVS:

NC_000013.11:g.51950116G>A
NG_008806.1:g.66379C>T
NM_000053.4:c.2621C>TMANE SELECT
NM_001005918.3:c.2135C>T
NM_001243182.2:c.2288C>T
NM_001330578.2:c.2387C>T
NM_001330579.2:c.2369C>T
NP_000044.2:p.Ala874Val
NP_001005918.1:p.Ala712Val
NP_001230111.1:p.Ala763Val
NP_001317507.1:p.Ala796Val
NP_001317508.1:p.Ala790Val
NC_000013.10:g.52524252G>A
NM_000053.3:c.2621C>T
P35670:p.Ala874Val

Protein change:

A712V; ALA874VAL

Links:

UniProtKB: P35670#VAR_000737; OMIM: 606882.0016; dbSNP: rs121907994

NCBI 1000 Genomes Browser:

rs121907994

Molecular consequence:

NM_000053.4:c.2621C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2135C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2288C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2387C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2369C>T - 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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024221	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12376745, 19419418
SCV000487224	Counsyl	no assertion criteria provided	Pathogenic (Oct 28, 2016)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9452121, 19419418, 16998622, 22735241, 27398169, 12544487, 11043508, 10544227, 22240481
SCV000626845	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10544227, 10721669, 11775208, 12376745, 12544487, 16998622, 18156766, 21707886, 22735241, 22240481, 22692182, 28492532
SCV000853123	SingHealth Duke-NUS Institute of Precision Medicine	no assertion criteria provided	Likely pathogenic (Jun 7, 2017)	germline	curation
SCV000916640	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22240481, 21645214, 27022412 Citation Link,
SCV001459723	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001712292	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002021406	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002496401	Provincial Medical Genetics Program of British Columbia, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2022)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003914808	Payam Genetics Center, General Welfare Department of North Khorasan Province	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2023)	germline	clinical testing
SCV004216314	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004810142	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004831416	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 10544227, 10721669, 11043508, 12376745, 12544487, 16998622, 18156766, 21645214, 21707886, 22240481, 22692182, 22735241, 25988284, 26269689, 27022412, 27398169, 28212618, 29381936, 30702195, 31743419, 31980526, 33763395, 25741868
SCV004847838	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12544487, 30655162, 22240481, 21707886, 22735241, 9452121, 19419418, 12376745, 27022412, 10721669, 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, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	6	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
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population
Iranian	germline	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification and analysis of mutations of the Wilson disease gene in Chinese population.

Wu Z, Wang N, Murong S, Lin M.

Chin Med J (Engl). 2000 Jan;113(1):40-3.

PubMed [citation]

PMID:: 11775208

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (28)

Details of each submission

From OMIM, SCV000024221.3

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

Description

For discussion of the ala874-to-val (A874V) mutation in the ATP7B gene that was found in compound heterozygous state in 2 sibs with Wilson disease (WND; 277900) by Takeshita et al. (2002), see 606882.0015.

Park et al. (2009) found heterozygosity for the A874V allele in 2 of 500 healthy Korean individuals, yielding a carrier frequency of 0.2% in this population.

#	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 Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (3)

#	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		1	not provided	not provided	not provided

From Counsyl, SCV000487224.2

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626845.7

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 874 of the ATP7B protein (p.Ala874Val). This variant is present in population databases (rs121907994, gnomAD 0.05%). This missense change has been observed in individuals with Wilson disease, with evidence of co-segregation with disease (PMID: 10544227, 10721669, 11775208, 12376745, 12544487, 16998622, 18156766, 21707886, 22735241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3851). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects 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 SingHealth Duke-NUS Institute of Precision Medicine, SCV000853123.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ATP7B c.2621C>T (p.Ala874Val) results in a non-conservative amino acid change in the P-type ATPase, A domain superfamily 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 6.9e-05 in 246236 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.2621C>T, has been reported in the literature in multiple individuals affected with Wilson Disease in both compound heterozygotes and homozygotes (Lee_2011, Dong_2016). 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 evaluating copper transport. The most pronounced variant effect results in 10-30% of normal copper transport rate activity (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic x2, VUS x1). 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 Natera, Inc., SCV001459723.1

#	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, SCV001712292.1

#	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 Revvity Omics, Revvity, SCV002021406.3

#	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 Provincial Medical Genetics Program of British Columbia, University of British Columbia, SCV002496401.1

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

From Payam Genetics Center, General Welfare Department of North Khorasan Province, SCV003914808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Iranian	1	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	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004216314.2

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004810142.1

#	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 All of Us Research Program, National Institutes of Health, SCV004831416.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (23)

Description

This missense variant replaces alanine with valine at codon 874 in the actuator domain 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 causes reduced protein expression, abnormal subcellular localization, and loss of copper transport activity (PMID: 22240481, 22692182). This variant has been reported in individuals affected with Wilson disease (PMID: 10544227, 10721669, 11043508, 12376745, 12544487, 16998622, 18156766, 21645214, 21707886, 22735241, 26269689, 25988284, 27022412, 27398169, 28212618, 29381936, 30702195, 31980526, 33763395). In many of these individuals, this variant was reported in the compound heterozygous state (PMID: 12376745, 21645214, 28212618, 29381936, 30702195, 31743419, 33763395) or homozygous state (PMID: 10721669, 18156766, 21645214, 22735241, 30702195). This variant has been identified in 17/249574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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		6	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847838.1

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

Description

The p.Ala874Val variant in ATP7B has been previously reported in many individuals with Wilson disease, including at least 2 compound heterozygotes and >10 compound heterozygotes, and segregated in at least 1 affected sibling (Chen 2019, Dong 2016, Kusuda 2000, Mihaylova 2012, Park 2009, Takeshita 2002, Tatsumi 2011, Yamaguchi 1998, Yoo 2002). It has been identified in 0.04% (8/17978) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, an in vitro functional study indicates that this variant results in reduced copper transport activity (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_Supporting, PS3_Supporting, PP1, PP4.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267218	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (3) [See all records that cite these PMIDs] 9452121, 22240481, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267218

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

PubMed (3)
[See all records that cite these PMIDs]

Last Updated: Oct 20, 2024

Relating variation to medicine