NM_000053.4(ATP7B):c.676C>T (p.Arg226Trp) AND Wilson disease

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Jul 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000354484.17

Allele description [Variation Report for NM_000053.4(ATP7B):c.676C>T (p.Arg226Trp)]

NM_000053.4(ATP7B):c.676C>T (p.Arg226Trp)

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.676C>T (p.Arg226Trp)

HGVS:

NC_000013.11:g.51974544G>A
NG_008806.1:g.41951C>T
NM_000053.4:c.676C>TMANE SELECT
NM_001005918.3:c.676C>T
NM_001243182.2:c.676C>T
NM_001330578.2:c.676C>T
NM_001330579.2:c.676C>T
NP_000044.2:p.Arg226Trp
NP_001005918.1:p.Arg226Trp
NP_001230111.1:p.Arg226Trp
NP_001317507.1:p.Arg226Trp
NP_001317508.1:p.Arg226Trp
NC_000013.10:g.52548680G>A
NM_000053.3:c.676C>T

Protein change:

R226W

Links:

dbSNP: rs749626601

NCBI 1000 Genomes Browser:

rs749626601

Molecular consequence:

NM_000053.4:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Wilson disease (WND)
Synonyms:: Wilson's disease
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
SCV000384684	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV003780762	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 22, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34400371, 28492532
SCV004216260	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005427975	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Mar 24, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34400371, 25741868
SCV005636284	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	143475	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

ATP7B variant spectrum in a French pediatric Wilson disease cohort.

Couchonnal E, Bouchard S, Sandahl TD, Pagan C, Lion-François L, Guillaud O, Habes D, Debray D, Lamireau T, Broué P, Fabre A, Vanlemmens C, Sobesky R, Gottrand F, Bridoux-Henno L, Belmalih A, Poujois A, Brunet AS, Lachaux A, Bost M.

Eur J Med Genet. 2021 Oct;64(10):104305. doi: 10.1016/j.ejmg.2021.104305. Epub 2021 Aug 13. Erratum in: Eur J Med Genet. 2021 Nov;64(11):104341. doi: 10.1016/j.ejmg.2021.104341.. Eur J Med Genet. 2022 Mar;65(3):104453. doi: 10.1016/j.ejmg.2022.104453..

PubMed [citation]

PMID:: 34400371

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000384684.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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, SCV003780762.4

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 226 of the ATP7B protein (p.Arg226Trp). This variant is present in population databases (rs749626601, gnomAD 0.03%). This missense change has been observed in individual(s) with Wilson disease (PMID: 34400371). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 312397). 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. 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, SCV004216260.2

#	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, SCV005427975.1

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

Description

This missense variant replaces arginine with tryptophan at codon 226 of the ATP7B protein. This variant is located in the extracellular metal binding domain 3 (a.a. 258-327) of the ATP protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in two children affected with Wilson disease in compound heterozygous state with another pathogenic variant in the same gene, as well as in one homozygous affected child (PMID: 34400371). This variant has been identified in 10/249438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV005636284.1

#	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

Last Updated: May 16, 2025

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