NM_000053.4(ATP7B):c.1374_1377del (p.Val459fs) AND Wilson disease

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

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 13, 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:: RCV000477923.6

Allele description

NM_000053.4(ATP7B):c.1374_1377del (p.Val459fs)

Gene:

ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_000053.4(ATP7B):c.1374_1377del (p.Val459fs)

HGVS:

NC_000013.11:g.51970658_51970661del
NG_008806.1:g.45834_45837del
NM_000053.4:c.1374_1377delMANE SELECT
NM_001005918.3:c.1374_1377del
NM_001243182.2:c.1041_1044del
NM_001330578.2:c.1374_1377del
NM_001330579.2:c.1374_1377del
NP_000044.2:p.Val459fs
NP_001005918.1:p.Val459fs
NP_001230111.1:p.Val348fs
NP_001317507.1:p.Val459fs
NP_001317508.1:p.Val459fs
NC_000013.10:g.52544794_52544797del
NC_000013.11:g.51970658_51970661delCACT
NM_000053.3:c.1374_1377delAGTG

Protein change:

V348fs

Links:

dbSNP: rs1060499593

NCBI 1000 Genomes Browser:

rs1060499593

Molecular consequence:

NM_000053.4:c.1374_1377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001005918.3:c.1374_1377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001243182.2:c.1041_1044del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330578.2:c.1374_1377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330579.2:c.1374_1377del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Wilson disease (WND)
Synonyms:: Wilson's disease; Hepatolenticular degeneration
Identifiers:: MONDO: MONDO:0010200; MedGen: C0019202; Orphanet: 905; OMIM: 277900

Recent activity

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ABC transporter ATP-binding protein [Desulfosudis oleivorans]
ABC transporter ATP-binding protein [Desulfosudis oleivorans]
gi|501125284|ref|WP_012174369.1|

Protein
Neckera pumila voucher MUB 9828 18S ribosomal RNA gene, partial sequence; intern...
Neckera pumila voucher MUB 9828 18S ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8S ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and 26S ribosomal RNA gene, partial sequence
gi|300432938|gb|HM105578.1|

Nucleotide
Neckera pennata isolate NF45 internal transcribed spacer 1, partial sequence; 5....
Neckera pennata isolate NF45 internal transcribed spacer 1, partial sequence; 5.8S ribosomal RNA gene, complete sequence; and internal transcribed spacer 2, partial sequence
gi|1677605421|gb|MN010515.1|

Nucleotide
Neckera pennata isolate NF48 internal transcribed spacer 1, partial sequence; 5....
Neckera pennata isolate NF48 internal transcribed spacer 1, partial sequence; 5.8S ribosomal RNA gene, complete sequence; and internal transcribed spacer 2, partial sequence
gi|1786514396|gb|MN854440.1|

Nucleotide
PREDICTED: Cucumis sativus protease 2 (LOC101207722), mRNA
PREDICTED: Cucumis sativus protease 2 (LOC101207722), mRNA
gi|1784858294|ref|XM_004139207.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000536836	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Feb 17, 2016)	germline	research
SCV004210681	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004679030	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10441329, 16283883, 28492532
SCV004837759	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848408	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing, research

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 Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536836.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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, SCV004210681.1

#	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 Invitae, SCV004679030.1

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

Description

This sequence change creates a premature translational stop signal (p.Val459Leufs*38) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 417911). 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 All of Us Research Program, National Institutes of Health, SCV004837759.1

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

Description

This variant deletes 4 nucleotides in exon 3 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with Wilson disease in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). 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		2	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848408.1

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

Description

The p.Val459LeufsX38 variant in ATP7B has not been previously reported in individuals with Wilson disease and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 459 and leads to a premature termination codon 38 amino acids downstream. This alteration is then 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: Jun 23, 2024

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