NM_000053.4(ATP7B):c.3008C>T (p.Ala1003Val) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: Mar 25, 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:: RCV000169109.18

Allele description [Variation Report for NM_000053.4(ATP7B):c.3008C>T (p.Ala1003Val)]

NM_000053.4(ATP7B):c.3008C>T (p.Ala1003Val)

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.3008C>T (p.Ala1003Val)

HGVS:

NC_000013.11:g.51946336G>A
NG_008806.1:g.70159C>T
NM_000053.4:c.3008C>TMANE SELECT
NM_001005918.3:c.2387C>T
NM_001243182.2:c.2675C>T
NM_001330578.2:c.2774C>T
NM_001330579.2:c.2756C>T
NP_000044.2:p.Ala1003Val
NP_001005918.1:p.Ala796Val
NP_001230111.1:p.Ala892Val
NP_001317507.1:p.Ala925Val
NP_001317508.1:p.Ala919Val
NC_000013.10:g.52520472G>A
NM_000053.2:c.3008C>T
NM_000053.3:c.3008C>T
P35670:p.Ala1003Val

Protein change:

A1003V

Links:

UniProtKB: P35670#VAR_009013; dbSNP: rs775055397

NCBI 1000 Genomes Browser:

rs775055397

Molecular consequence:

NM_000053.4:c.3008C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2387C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2675C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2774C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2756C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000220309	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 14, 2014)	unknown	literature only	PubMed (5) [See all records that cite these PMIDs] 23333878, 24094725, 22484412, 17264425, 10502776 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001361702	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 9, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10544227, 23518715, 25982861 Citation Link,
SCV001469299	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Oct 11, 2020)	germline	clinical testing
SCV001592608	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10544227, 17264425, 31059521, 12885331, 21610751, 26799313, 28492532
SCV001977286	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]
SCV002086833	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 5, 2018)	germline	clinical testing
SCV002811654	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004032255	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2023)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216277	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004806315	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847816	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 (10) [See all records that cite these PMIDs] 24094725, 23333878, 25982861, 17264425, 10544227, 30120852, 26207595, 23518715, 17823867, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	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

Citations

PubMed

Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis.

Lepori MB, Zappu A, Incollu S, Dessì V, Mameli E, Demelia L, Nurchi AM, Gheorghe L, Maggiore G, Sciveres M, Leuzzi V, Indolfi G, Bonafé L, Casali C, Angeli P, Barone P, Cao A, Loudianos G.

Mol Cell Probes. 2012 Aug;26(4):147-50. doi: 10.1016/j.mcp.2012.03.007. Epub 2012 Mar 29.

PubMed [citation]

PMID:: 22484412

Molecular characterization of wilson disease in the Sardinian population--evidence of a founder effect.

Loudianos G, Dessi V, Lovicu M, Angius A, Figus A, Lilliu F, De Virgiliis S, Nurchi AM, Deplano A, Moi P, Pirastu M, Cao A.

Hum Mutat. 1999;14(4):294-303.

PubMed [citation]

PMID:: 10502776

See all PubMed Citations (17)

Details of each submission

From Counsyl, SCV000220309.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

#	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, SCV001361702.1

#	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.3008C>T (p.Ala1003Val) results in a non-conservative amino acid change in 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 3.3e-05 in 240390 control chromosomes (gnomAD). c.3008C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Loudianos_1999, Coffey_2013, Guggilla_2015). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469299.1

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

From Invitae, SCV001592608.4

#	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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1003 of the ATP7B protein (p.Ala1003Val). This variant is present in population databases (rs775055397, gnomAD 0.03%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17264425, 31059521). ClinVar contains an entry for this variant (Variation ID: 188781). 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%. This variant disrupts the p.Ala1003 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12885331, 21610751, 26799313; Invitae). 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 Genome-Nilou Lab, SCV001977286.1

#	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., SCV002086833.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002811654.1

#	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, SCV004032255.2

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

Description

Criteria applied: PM3_VSTR,PS4_MOD,PP3; Identified as compund heterozygous with NM_000053.4:c.2906G>A

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

From Baylor Genetics, SCV004216277.1

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806315.1

#	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, SCV004847816.1

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

Description

The p.Ala1003Val variant in ATP7B has been reported in several individuals with Wilson disease, including at least 2 homozygotes and 1 compound heterozygote; however, in the majority of studies, allelic data (cis/trans, homozygous or compound heterozygous state) was not reported (Mukherjee 2014, Simsek 2013, Guggilla 2015, Santhosh 2006, Loudianos 1999, Kumari 2018, Gomes 2016, Gupta 2007, Coffey 2013). This variant has also been identified in 0.02% (8/29742) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). A pathogenic variant affecting the same amino acid position, p.Ala1003Thr, has been previously reported in many individuals with Wilson disease. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. 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 Wilson disease. ACMG/AMP criteria applied: PM2, PM5, PP3, PP4, PM3_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: Apr 20, 2024

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