NM_000053.4(ATP7B):c.3316G>A (p.Val1106Ile) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jun 13, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000586649.2

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)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000694444Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jun 13, 2019)
germlineclinical testing

PubMed (22)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease.

Wu ZY, Wang N, Lin MT, Fang L, Murong SX, Yu L.

Arch Neurol. 2001 Jun;58(6):971-6.

PubMed [citation]
PMID:
11405812

Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease.

Liu XQ, Zhang YF, Liu TT, Hsiao KJ, Zhang JM, Gu XF, Bao KR, Yu LH, Wang MX.

World J Gastroenterol. 2004 Feb 15;10(4):590-3.

PubMed [citation]
PMID:
14966923
PMCID:
PMC4716986
See all PubMed Citations (22)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694444.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (22)

Description

Variant summary: ATP7B c.3316G>A (p.Val1106Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 280988 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The frequency within the East Asian subpopulation is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (WD) (0.0017 vs. 0.0054), allowing no conclusion about variant significance. In the literature, this variant has been reported in a large number of WD patients, primarily of Asian (Chinese and Korean) origin, but without strong evidence for pathogenicity (i.e. the presence- and phase of co-occurring variants were not specified in many of these reports, and cosegregation with the disease was not reported). This variant has also been reported to be found in the same allele with other pathogenic variants (Wu_2001, Dong_2016), providing evidence against pathogenicity. However, a small case-control study showed an odds ratio (OR) of ~10.5 (95%CI=1.36-79.9), suggesting that this variant may be a risk allele for Wilson disease (Dong_2016). Larger studies are required to confirm this finding. A functional assay showed no significant reduction in the variant's ability to rescue the delta-ccc2 yeast strain (i.e. the strain lacking the yeast gene ortholog), furthermore, confocal images showed that the variant protein localized to the same trans-Golgi network in COS-7 cells as the wild-type ATP7B (Park_2007). However, another study noted that the activity of Cu-ATPase in lymphocytes from a compound heterozygous patient was decreased by ~45% (Liu_2004). Furthermore, another missense variant affecting the same residue (V1106D) was reported as functionally deficient (PMID: 18203200). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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

Last Updated: Nov 27, 2021

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