NM_000053.4(ATP7B):c.1924G>C (p.Asp642His) AND Wilson disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 12, 2021
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:: RCV000169521.9

Allele description

NM_000053.4(ATP7B):c.1924G>C (p.Asp642His)

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.1924G>C (p.Asp642His)

HGVS:

NC_000013.11:g.51961859C>G
NG_008806.1:g.54636G>C
NM_000053.4:c.1924G>CMANE SELECT
NM_001005918.3:c.1869+3013G>C
NM_001243182.2:c.1591G>C
NM_001330578.2:c.1924G>C
NM_001330579.2:c.1869+3013G>C
NP_000044.2:p.Asp642His
NP_001230111.1:p.Asp531His
NP_001317507.1:p.Asp642His
NC_000013.10:g.52535995C>G
NM_000053.3:c.1924G>C
P35670:p.Asp642His

Protein change:

D531H

Links:

UniProtKB: P35670#VAR_000713; dbSNP: rs72552285

NCBI 1000 Genomes Browser:

rs72552285

Molecular consequence:

NM_001005918.3:c.1869+3013G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001330579.2:c.1869+3013G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000053.4:c.1924G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.1591G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.1924G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on protein subcellular localization [Variation Ontology: 0033]

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
SCV000220995	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Dec 29, 2014)	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 21682854, 21610751, 24706876, 18203200, 17919502, 9671269, 22308153, 18483695 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000626833	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 12, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18483695, 21610751, 21682854, 22308153, 24706876, 29540233, 18203200, 28492532
SCV001810287	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]
SCV002024426	PerkinElmer Genomics	no assertion criteria provided	Likely pathogenic (May 17, 2021)	germline	clinical testing
SCV002087859	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Apr 2, 2021)	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	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	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.

de Bie P, van de Sluis B, Burstein E, van de Berghe PV, Muller P, Berger R, Gitlin JD, Wijmenga C, Klomp LW.

Gastroenterology. 2007 Oct;133(4):1316-26. Epub 2007 Jul 25.

PubMed [citation]

PMID:: 17919502
PMCID:: PMC2857755

Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.

Loudianos G, Dessì V, Lovicu M, Angius A, Nurchi A, Sturniolo GC, Marcellini M, Zancan L, Bragetti P, Akar N, Yagci R, Vegnente A, Cao A, Pirastu M.

Hum Mutat. 1998;12(2):89-94.

PubMed [citation]

PMID:: 9671269

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000220995.1

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

#	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 Invitae, SCV000626833.2

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 642 of the ATP7B protein (p.Asp642His). This variant is present in population databases (rs72552285, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson syndrome and a copper metabolism disorder and Wilson disease (PMID: 18483695, 21610751, 21682854, 22308153, 24706876, 29540233; Invitae). In at least one individual the data is consistent with the variant 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: 189109). 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 does not substantially affect ATP7B function (PMID: 18203200). 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, SCV001810287.1

#	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 PerkinElmer Genomics, SCV002024426.1

#	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 Natera, Inc., SCV002087859.1

#	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

Last Updated: Dec 11, 2022

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