NM_000053.4(ATP7B):c.2072G>T (p.Gly691Val) AND Wilson disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 13, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000671031.5

Allele description [Variation Report for NM_000053.4(ATP7B):c.2072G>T (p.Gly691Val)]

NM_000053.4(ATP7B):c.2072G>T (p.Gly691Val)

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.2072G>T (p.Gly691Val)
HGVS:
  • NC_000013.11:g.51960197C>A
  • NG_008806.1:g.56298G>T
  • NM_000053.4:c.2072G>TMANE SELECT
  • NM_001005918.3:c.1870-2590G>T
  • NM_001243182.1:c.1739G>T
  • NM_001330578.1:c.2072G>T
  • NM_001330579.2:c.1870-1653G>T
  • NP_000044.2:p.Gly691Val
  • NP_001230111.1:p.Gly580Val
  • NP_001317507.1:p.Gly691Val
  • NC_000013.10:g.52534333C>A
  • NM_000053.3:c.2072G>T
Protein change:
G580V
Links:
dbSNP: rs1555291801
NCBI 1000 Genomes Browser:
rs1555291801
Molecular consequence:
  • NM_001005918.3:c.1870-2590G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001330579.2:c.1870-1653G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000053.4:c.2072G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243182.1:c.1739G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330578.1:c.2072G>T - 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
SCV000795969Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 26, 2017)
unknownclinical testing

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

Citation Link,

SCV000825523Invitaecriteria provided, single submitter
Pathogenic
(Nov 27, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001158498ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(May 13, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins.

Paradisi I, De Freitas L, Arias S.

Eur J Med Genet. 2015 Feb;58(2):59-65. doi: 10.1016/j.ejmg.2014.12.007. Epub 2014 Dec 12.

PubMed [citation]
PMID:
25497208

Early and severe liver disease associated with homozygosity for an exon 7 mutation, G691R, in Wilson's disease.

Barada K, Nemer G, ElHajj II, Touma J, Cortas N, Boustany RM, Usta J.

Clin Genet. 2007 Sep;72(3):264-7. No abstract available.

PubMed [citation]
PMID:
17718866
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000795969.1

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

From Invitae, SCV000825523.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glycine with valine at codon 691 of the ATP7B protein (p.Gly691Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 25497208). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Gly691Arg) has been determined to be likely pathogenic (PMID: 17718866, 23389864, 9671269). This suggests that the glycine residue is critical for ATP7B protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158498.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ATP7B c.2072G>T; p.Gly691Val variant is reported in the literature in the homozygous or trans-heterozygous state in individuals affected with Wilson disease (Paradisi 2015). This variant is reported in ClinVar (Variation ID: 555245), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 691 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.2071G>A; p.Gly691Arg) has been reported in individuals with Wilson disease (Loudianos 1998). Based on available information, the p.Gly691Val variant is considered to be likely pathogenic. References: Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Paradisi I et al. Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins. Eur J Med Genet. 2015 Feb;58(2):59-65.

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

Last Updated: May 10, 2021

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