NM_000053.4(ATP7B):c.3551T>C (p.Ile1184Thr) AND Wilson disease

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 17, 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:: RCV001254597.15

Allele description [Variation Report for NM_000053.4(ATP7B):c.3551T>C (p.Ile1184Thr)]

NM_000053.4(ATP7B):c.3551T>C (p.Ile1184Thr)

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.3551T>C (p.Ile1184Thr)

HGVS:

NC_000013.11:g.51941086A>G
NG_008806.1:g.75409T>C
NM_000053.4:c.3551T>CMANE SELECT
NM_001005918.3:c.2930T>C
NM_001243182.2:c.3218T>C
NM_001330578.2:c.3317T>C
NM_001330579.2:c.3299T>C
NP_000044.2:p.Ile1184Thr
NP_001005918.1:p.Ile977Thr
NP_001230111.1:p.Ile1073Thr
NP_001317507.1:p.Ile1106Thr
NP_001317508.1:p.Ile1100Thr
NC_000013.10:g.52515222A>G
NM_000053.3:c.3551T>C
NM_001005918.3:c.2930T>C

Protein change:

I1073T

Links:

dbSNP: rs755817220

NCBI 1000 Genomes Browser:

rs755817220

Molecular consequence:

NM_000053.4:c.3551T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2930T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.3218T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.3317T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.3299T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001430587	Hadassah Hebrew University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 20, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 33223529
SCV001563236	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23518715, 25678388, 32770663, 28492532
SCV001977551	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086805	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jul 30, 2021)	germline	clinical testing
SCV004805123	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 17, 2024)	germline	research	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child.

Mor-Shaked H, Rips J, Gershon Naamat S, Reich A, Elpeleg O, Meiner V, Harel T.

Eur J Hum Genet. 2021 Mar;29(3):455-462. doi: 10.1038/s41431-020-00756-y. Epub 2020 Nov 22.

PubMed [citation]

PMID:: 33223529
PMCID:: PMC7940654

A genetic study of Wilson's disease in the United Kingdom.

Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, Klaffke S, Joyce CJ, Dhawan A, Hadzic N, Mieli-Vergani G, Kirk R, Elizabeth Allen K, Nicholl D, Wong S, Griffiths W, Smithson S, Giffin N, Taha A, Connolly S, Gillett GT, Tanner S, et al.

Brain. 2013 May;136(Pt 5):1476-87. doi: 10.1093/brain/awt035. Epub 2013 Mar 21.

PubMed [citation]

PMID:: 23518715
PMCID:: PMC3634195

See all PubMed Citations (6)

Details of each submission

From Hadassah Hebrew University Medical Center, SCV001430587.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001563236.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1184 of the ATP7B protein (p.Ile1184Thr). This variant is present in population databases (rs755817220, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 23518715, 25678388, 32770663). 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: 977075). 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 not expected to disrupt ATP7B protein function. 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.

#	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, SCV001977551.1

#	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 Natera, Inc., SCV002086805.1

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805123.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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: Sep 29, 2024

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