NM_000053.4(ATP7B):c.3316G>A (p.Val1106Ile) AND Wilson disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 10, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000674801.5

Allele description [Variation Report for NM_000053.4(ATP7B):c.3316G>A (p.Val1106Ile)]

NM_000053.4(ATP7B):c.3316G>A (p.Val1106Ile)

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.3316G>A (p.Val1106Ile)
HGVS:
  • NC_000013.11:g.51942482C>T
  • NG_008806.1:g.74013G>A
  • NM_000053.4:c.3316G>AMANE SELECT
  • NM_001005918.3:c.2695G>A
  • NM_001243182.2:c.2983G>A
  • NM_001330578.2:c.3082G>A
  • NM_001330579.2:c.3064G>A
  • NP_000044.2:p.Val1106Ile
  • NP_001005918.1:p.Val899Ile
  • NP_001230111.1:p.Val995Ile
  • NP_001317507.1:p.Val1028Ile
  • NP_001317508.1:p.Val1022Ile
  • NC_000013.10:g.52516618C>T
  • NM_000053.2:c.3316G>A
  • NM_000053.3:c.3316G>A
Protein change:
V1022I
Links:
dbSNP: rs541208827
NCBI 1000 Genomes Browser:
rs541208827
Molecular consequence:
  • NM_000053.4:c.3316G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005918.3:c.2695G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243182.2:c.2983G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330578.2:c.3082G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330579.2:c.3064G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000800200Counsylcriteria provided, single submitter
Likely pathogenic
(May 25, 2018)
unknownclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000915634Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Oct 5, 2018)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV001411757Invitaecriteria provided, single submitter
Pathogenic
(Sep 10, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001977133Nilou-Genome Labcriteria provided, single submitter
Likely pathogenic
(Aug 10, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease.

Cheng N, Wang H, Wu W, Yang R, Liu L, Han Y, Guo L, Hu J, Xu L, Zhao J, Han Y, Liu Q, Li K, Wang X, Chen W.

Clin Genet. 2017 Jul;92(1):69-79. doi: 10.1111/cge.12951. Epub 2017 Feb 16.

PubMed [citation]
PMID:
27982432

A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism.

Schushan M, Bhattacharjee A, Ben-Tal N, Lutsenko S.

Metallomics. 2012 Jul;4(7):669-78. doi: 10.1039/c2mt20025b. Epub 2012 Jun 13.

PubMed [citation]
PMID:
22692182
PMCID:
PMC6365107
See all PubMed Citations (18)

Details of each submission

From Counsyl, SCV000800200.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915634.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

The ATP7B c.3316G>A (p.Val1106Ile) variant is a missense variant that has been widely reported in association with Wilson disease, primarily in individuals of Asian ancestry. Across a selection of the available literature, it was reported in a heterozygous state in at least 25 affected individuals (Wu et al. 2001; Liu et al. 2004; Li et al. 2011; Abuduxikuer et al. 2014; Mukherjee et al. 2014; Tu et al. 2015; Zong and Kong 2015; Dong et al. 2016; Hua et al. 2016; Poon et al. 2016; Yu et al. 2017). The presence and phase of additional variants were not clearly reported in many cases, but at least seven patients were compound heterozygous. In at least one case, the p.Val1106Ile variant was found in cis with a known pathogenic variant. These reports include a small case-control study, which found an OR of 10.44 (95% CI 1.36-79.97, corrected for multiple comparisons) for this variant (Dong et al. 2016). The p.Val1106Ile variant was identified in one out of 663 ethnically matched control individuals and is reported at a frequency of 0.001802 in the East Asian population of the Genome Aggregation Database. Functional studies in COS-7 cells suggested the variant, which is located in the ATP binding domain, does not impair protein localization, and studies in yeast indicated a minor impact on transport function (Park et al. 2007). However, lymphocytes from a compound heterozygous carrier showed ~45% of normal copper ATPase activity (Liu et al. 2004). Based on the collective evidence, the p.Val1106Ile variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001411757.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces valine with isoleucine at codon 1106 of the ATP7B protein (p.Val1106Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs541208827, ExAC 0.2%). This variant has been reported in combination with other ATP7B variants in several individuals affected with Wilson disease (PMID: 14966923, 27022412, 28212618, 26483271, 30702195). ClinVar contains an entry for this variant (Variation ID: 495414). 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. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Nilou-Genome Lab, SCV001977133.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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