NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His) AND Wilson disease

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Aug 13, 2023
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:: RCV000666672.12

Allele description [Variation Report for NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His)]

NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His)

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.3452G>A (p.Arg1151His)

HGVS:

NC_000013.11:g.51941185C>T
NG_008806.1:g.75310G>A
NM_000053.4:c.3452G>AMANE SELECT
NM_001005918.3:c.2831G>A
NM_001243182.2:c.3119G>A
NM_001330578.2:c.3218G>A
NM_001330579.2:c.3200G>A
NP_000044.2:p.Arg1151His
NP_001005918.1:p.Arg944His
NP_001230111.1:p.Arg1040His
NP_001317507.1:p.Arg1073His
NP_001317508.1:p.Arg1067His
NC_000013.10:g.52515321C>T
NM_000053.2:c.3452G>A
NM_000053.3:c.3452G>A

Protein change:

R1040H

Links:

dbSNP: rs377297166

NCBI 1000 Genomes Browser:

rs377297166

Molecular consequence:

NM_000053.4:c.3452G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2831G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.3119G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.3218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.3200G>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
SCV000791002	Counsyl	no assertion criteria provided	Likely pathogenic (Oct 9, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27982432, 27398169, 15205462, 10544227, 27022412, 21219664
SCV001455587	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002292010	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 11, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15205462, 17949296, 21645214, 23333878, 27398169, 10544227, 30655162, 28492532
SCV004216359	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004829545	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 16, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10544227, 15205462, 21219664, 27022412, 27398169, 27982432, 35222532, 36253962, 25741868

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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	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin.

Lepori MB, Lovicu M, Dessi V, Zappu A, Incollu S, Zancan L, Giacchino R, Iorio R, Vajro P, Maggiore G, Marcellini M, Barbera C, Pellecchia MT, Simonetti R, Kostic V, Farci AM, Solinas A, De Virgiliis S, Cao A, Loudianos G.

Genet Test. 2007 Fall;11(3):328-32.

PubMed [citation]

PMID:: 17949296

Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.

Lee BH, Kim JH, Lee SY, Jin HY, Kim KJ, Lee JJ, Park JY, Kim GH, Choi JH, Kim KM, Yoo HW.

Liver Int. 2011 Jul;31(6):831-9. doi: 10.1111/j.1478-3231.2011.02503.x. Epub 2011 Mar 13. Erratum in: Liver Int. 2011 Sep;31(8):1242.

PubMed [citation]

PMID:: 21645214

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000791002.2

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

#	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 Natera, Inc., SCV001455587.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002292010.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. Experimental studies have shown that this missense change affects ATP7B function (PMID: 15205462). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17949296, 21645214, 23333878, 27398169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1151 of the ATP7B protein (p.Arg1151His). This variant is present in population databases (rs377297166, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 30655162). ClinVar contains an entry for this variant (Variation ID: 495415).

#	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, SCV004216359.1

#	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 All of Us Research Program, National Institutes of Health, SCV004829545.1

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

Description

This missense variant, c.3452G>A, replaces arginine with histidine at codon 1151 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 showed that this variant has a 1.3 fold reduced affinity to ATP compared with wild-type (PMID: 15205462). This variant has been reported in many individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 21219664, 27022412, 27398169, 27982432). In one affected individual, this variant was observed in the compound heterozygous state with a second pathogenic variant (PMID: 10544227), indicating that this variant contributes to disease. Additionally, in three affected individuals, a second co-occurring pathogenic ATP7B variant was detected, however, it is unknown whether these variants are in cis or trans (PMID: 27398169, 35222532, 36253962). This variant has been identified in 3/249588 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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