NM_000053.4(ATP7B):c.1147C>T (p.Gln383Ter) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 9, 2023
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:: RCV001385918.5

Allele description [Variation Report for NM_000053.4(ATP7B):c.1147C>T (p.Gln383Ter)]

NM_000053.4(ATP7B):c.1147C>T (p.Gln383Ter)

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.1147C>T (p.Gln383Ter)

HGVS:

NC_000013.11:g.51974073G>A
NG_008806.1:g.42422C>T
NM_000053.4:c.1147C>TMANE SELECT
NM_001005918.3:c.1147C>T
NM_001243182.2:c.814C>T
NM_001330578.2:c.1147C>T
NM_001330579.2:c.1147C>T
NP_000044.2:p.Gln383Ter
NP_001005918.1:p.Gln383Ter
NP_001230111.1:p.Gln272Ter
NP_001317507.1:p.Gln383Ter
NP_001317508.1:p.Gln383Ter
NC_000013.10:g.52548209G>A

Protein change:

Q272*

Links:

dbSNP: rs2140071850

NCBI 1000 Genomes Browser:

rs2140071850

Molecular consequence:

NM_000053.4:c.1147C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001005918.3:c.1147C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243182.2:c.814C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330578.2:c.1147C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330579.2:c.1147C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001585936	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10441329, 16283883, 28492532
SCV004848409	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 (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001585936

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004848409

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 (1)
[See all records that cite this PMID]

Help

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

Citations

PubMed

Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.

Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC.

Hum Mol Genet. 1999 Sep;8(9):1665-71.

PubMed [citation]

PMID:: 10441329

Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.

Gromadzka G, Schmidt HH, Genschel J, Bochow B, Rodo M, Tarnacka B, Litwin T, Chabik G, Członkowska A.

Clin Genet. 2005 Dec;68(6):524-32.

PubMed [citation]

PMID:: 16283883

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001585936.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1073036). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln383*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883).

#	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, SCV004848409.1

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

Description

The p.Gln383X variant in ATP7B has not been previously reported in individuals with Wilson disease and was absent from large pouplation studies. This nonsense variant leads to a premature termination codon at position 383, which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. 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 recessive Wilson disease. ACMG/AMP Criteria applied: PVS1, PM2.

#	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 1, 2024

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