NM_000053.4(ATP7B):c.2668G>A (p.Val890Met) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Apr 13, 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:: RCV000169535.23

Allele description [Variation Report for NM_000053.4(ATP7B):c.2668G>A (p.Val890Met)]

NM_000053.4(ATP7B):c.2668G>A (p.Val890Met)

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.2668G>A (p.Val890Met)

HGVS:

NC_000013.11:g.51950069C>T
NG_008806.1:g.66426G>A
NM_000053.4:c.2668G>AMANE SELECT
NM_001005918.3:c.2182G>A
NM_001243182.2:c.2335G>A
NM_001330578.2:c.2434G>A
NM_001330579.2:c.2416G>A
NP_000044.2:p.Val890Met
NP_001005918.1:p.Val728Met
NP_001230111.1:p.Val779Met
NP_001317507.1:p.Val812Met
NP_001317508.1:p.Val806Met
NC_000013.10:g.52524205C>T
NM_000053.3:c.2668G>A
P35670:p.Val890Met

Protein change:

V728M

Links:

UniProtKB: P35670#VAR_023023; dbSNP: rs786204718

NCBI 1000 Genomes Browser:

rs786204718

Molecular consequence:

NM_000053.4:c.2668G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2416G>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
SCV000221015	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 8, 2015)	unknown	literature only	PubMed (7) [See all records that cite these PMIDs] 23486543, 23235335, 20517649, 11216666, 14986826, 22308153, 22677543 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000845443	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2024)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000916634	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 2, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23235335, 27982432, 11216666, 27022412, 20517649, 14986826, 23486543 Citation Link,
SCV001228417	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11216666, 14986826, 22308153, 22484412, 22677543, 23235335, 27022412, 29637721, 29979436, 28492532
SCV001810286	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002087840	Natera, Inc.	no assertion criteria provided	Pathogenic (Apr 27, 2020)	germline	clinical testing
SCV004216415	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 23, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004845490	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 11216666, 14986826, 20517649, 20958917, 22308153, 22484412, 22677543, 23235335, 23486543, 27022412, 27982432, 28753182, 29637721, 30230192, 33879678, 34002136, 34240825, 34400371, 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	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing
not provided	inherited	yes	1	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

Familial screening of children with Wilson disease: Necessity of screening in previous generation and screening methods.

Li H, Liu L, Li Y, He S, Liu Y, Li J, Tao R, Li W, Shang S.

Medicine (Baltimore). 2018 Jul;97(27):e11405. doi: 10.1097/MD.0000000000011405.

PubMed [citation]

PMID:: 29979436
PMCID:: PMC6076046

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 (21)

Details of each submission

From Counsyl, SCV000221015.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000845443.2

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916634.1

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

Description

Variant summary: ATP7B c.2668G>A (p.Val890Met) 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 allele was found at a frequency of 1.4e-05 in 277226 control chromosomes. c.2668G>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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001228417.5

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 890 of the ATP7B protein (p.Val890Met). This variant is present in population databases (rs786204718, gnomAD 0.004%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11216666, 14986826, 22308153, 22484412, 22677543, 23235335, 27022412, 29637721, 29979436; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189121). 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%. 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, SCV001810286.1

#	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., SCV002087840.1

#	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 Baylor Genetics, SCV004216415.2

#	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, SCV004845490.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (19)

Description

This missense variant replaces valine with methionine at codon 890 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with Wilson disease (PMID: 11216666, 14986826, 20517649, 22308153, 20958917, 22484412, 22677543, 23235335, 23486543, 27022412, 28753182, 27982432, 29637721, 30230192, 33879678, 34240825, 34002136, 34400371). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 30230192, 33879678, 34002136) and homozygous state (PMID: 34400371). This variant has been identified in 5/280992 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		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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