NM_000053.4(ATP7B):c.2827G>A (p.Gly943Ser) AND Wilson disease

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

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000004060.9

Allele description [Variation Report for NM_000053.4(ATP7B):c.2827G>A (p.Gly943Ser)]

NM_000053.4(ATP7B):c.2827G>A (p.Gly943Ser)

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.2827G>A (p.Gly943Ser)
HGVS:
  • NC_000013.11:g.51949700C>T
  • NG_008806.1:g.66795G>A
  • NM_000053.4:c.2827G>AMANE SELECT
  • NM_001005918.3:c.2244+307G>A
  • NM_001243182.2:c.2494G>A
  • NM_001330578.2:c.2593G>A
  • NM_001330579.2:c.2575G>A
  • NP_000044.2:p.Gly943Ser
  • NP_001230111.1:p.Gly832Ser
  • NP_001317507.1:p.Gly865Ser
  • NP_001317508.1:p.Gly859Ser
  • NC_000013.10:g.52523836C>T
  • NM_000053.2:c.2827G>A
  • NM_000053.3:c.2827G>A
  • P35670:p.Gly943Ser
Protein change:
G832S; GLY943SER
Links:
UniProtKB: P35670#VAR_000745; OMIM: 606882.0013; dbSNP: rs28942076
NCBI 1000 Genomes Browser:
rs28942076
Molecular consequence:
  • NM_001005918.3:c.2244+307G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000053.4:c.2827G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243182.2:c.2494G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330578.2:c.2593G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330579.2:c.2575G>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
SCV000024226OMIMno assertion criteria providedPathogenic
(Feb 1, 1995)
germlineliterature only

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

SCV000694432Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 16, 2016)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000793725Counsylno assertion criteria providedLikely pathogenic
(Jan 22, 2019)
unknownclinical testing

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

SCV000959367Invitaecriteria provided, single submitter
Pathogenic
(Jul 20, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001977301Nilou-Genome Labcriteria provided, single submitter
Pathogenic
(Aug 10, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations.

Simsek Papur O, Akman SA, Cakmur R, Terzioglu O.

Eur J Med Genet. 2013 Apr;56(4):175-9. doi: 10.1016/j.ejmg.2013.01.003. Epub 2013 Jan 17.

PubMed [citation]
PMID:
23333878

Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.

Figus A, Angius A, Loudianos G, Bertini C, Dessi V, Loi A, Deiana M, Lovicu M, Olla N, Sole G, et al.

Am J Hum Genet. 1995 Dec;57(6):1318-24.

PubMed [citation]
PMID:
8533760
PMCID:
PMC1801406
See all PubMed Citations (20)

Details of each submission

From OMIM, SCV000024226.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In patients with Wilson disease (WND; 277900), Thomas et al. (1995) identified a GGT-to-AGT change in the ATP7B gene, resulting in a gly943-to-ser mutation.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694432.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: c.2827G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 2/120362 control chromosomes at a frequency of 0.0000166, which does not exceed maximal expected frequency of a pathogenic allele (0.0054006). This variant has been reported in multiple affected individuals and functional studies showed that variant had impaired ability to complement the high-affinity iron-uptake deficiency of the yeast mutant, and despite the normal localization of variant to the Golgi network of CHO cells, variant was non-responsive to copper and exhibited no obvious copper-induced redistribution (Forbes_1998 and 2000). Taken together, this variant was classified as a Pathogenic.

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

From Counsyl, SCV000793725.2

#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 Invitae, SCV000959367.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces glycine with serine at codon 943 of the ATP7B protein (p.Gly943Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs28942076, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 7626145, 11243728, 27022412). ClinVar contains an entry for this variant (Variation ID: 3856). Experimental studies have shown that this missense change disrupts redistribution of ATP7B protein in response to copper (PMID: 10942420). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly943 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 28212618, 16603785, 27930511, 16088907), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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, SCV001977301.1

#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: Dec 2, 2021

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