NM_000053.4(ATP7B):c.748G>A (p.Gly250Arg) AND Wilson disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003066827.3

Allele description

NM_000053.4(ATP7B):c.748G>A (p.Gly250Arg)

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.748G>A (p.Gly250Arg)

HGVS:

NC_000013.11:g.51974472C>T
NG_008806.1:g.42023G>A
NM_000053.4:c.748G>AMANE SELECT
NM_001005918.3:c.748G>A
NM_001243182.2:c.748G>A
NM_001330578.2:c.748G>A
NM_001330579.2:c.748G>A
NM_001406511.1:c.748G>A
NM_001406512.1:c.748G>A
NM_001406513.1:c.748G>A
NM_001406514.1:c.748G>A
NM_001406515.1:c.748G>A
NM_001406516.1:c.748G>A
NM_001406517.1:c.652G>A
NM_001406518.1:c.652G>A
NM_001406519.1:c.748G>A
NM_001406520.1:c.748G>A
NM_001406521.1:c.748G>A
NM_001406522.1:c.748G>A
NM_001406523.1:c.748G>A
NM_001406524.1:c.748G>A
NM_001406525.1:c.748G>A
NM_001406526.1:c.748G>A
NM_001406527.1:c.748G>A
NM_001406528.1:c.748G>A
NM_001406530.1:c.652G>A
NM_001406531.1:c.748G>A
NM_001406532.1:c.748G>A
NM_001406534.1:c.748G>A
NM_001406535.1:c.748G>A
NM_001406536.1:c.652G>A
NM_001406537.1:c.748G>A
NM_001406538.1:c.748G>A
NM_001406539.1:c.652G>A
NM_001406540.1:c.748G>A
NM_001406541.1:c.748G>A
NM_001406542.1:c.748G>A
NM_001406543.1:c.652G>A
NM_001406544.1:c.652G>A
NM_001406545.1:c.748G>A
NM_001406546.1:c.748G>A
NM_001406547.1:c.748G>A
NM_001406548.1:c.748G>A
NP_000044.2:p.Gly250Arg
NP_001005918.1:p.Gly250Arg
NP_001230111.1:p.Gly250Arg
NP_001317507.1:p.Gly250Arg
NP_001317508.1:p.Gly250Arg
NP_001393440.1:p.Gly250Arg
NP_001393441.1:p.Gly250Arg
NP_001393442.1:p.Gly250Arg
NP_001393443.1:p.Gly250Arg
NP_001393444.1:p.Gly250Arg
NP_001393445.1:p.Gly250Arg
NP_001393446.1:p.Gly218Arg
NP_001393447.1:p.Gly218Arg
NP_001393448.1:p.Gly250Arg
NP_001393449.1:p.Gly250Arg
NP_001393450.1:p.Gly250Arg
NP_001393451.1:p.Gly250Arg
NP_001393452.1:p.Gly250Arg
NP_001393453.1:p.Gly250Arg
NP_001393454.1:p.Gly250Arg
NP_001393455.1:p.Gly250Arg
NP_001393456.1:p.Gly250Arg
NP_001393457.1:p.Gly250Arg
NP_001393459.1:p.Gly218Arg
NP_001393460.1:p.Gly250Arg
NP_001393461.1:p.Gly250Arg
NP_001393463.1:p.Gly250Arg
NP_001393464.1:p.Gly250Arg
NP_001393465.1:p.Gly218Arg
NP_001393466.1:p.Gly250Arg
NP_001393467.1:p.Gly250Arg
NP_001393468.1:p.Gly218Arg
NP_001393469.1:p.Gly250Arg
NP_001393470.1:p.Gly250Arg
NP_001393471.1:p.Gly250Arg
NP_001393472.1:p.Gly218Arg
NP_001393473.1:p.Gly218Arg
NP_001393474.1:p.Gly250Arg
NP_001393475.1:p.Gly250Arg
NP_001393476.1:p.Gly250Arg
NP_001393477.1:p.Gly250Arg
NC_000013.10:g.52548608C>T

Protein change:

G218R

Molecular consequence:

NM_000053.4:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406511.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406512.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406513.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406514.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406515.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406516.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406517.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406518.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406519.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406520.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406521.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406522.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406523.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406524.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406525.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406526.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406527.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406528.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406530.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406531.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406532.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406534.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406535.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406536.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406537.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406538.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406539.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406540.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406541.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406542.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406543.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406544.1:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406545.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406546.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406547.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406548.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV003447403	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 20, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27398169, 34470610, 28492532
SCV004829380	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27398169, 30702195, 34470610, 36253962, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003447403

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 20, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004829380

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 4, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutational analysis of ATP7B in Chinese Wilson disease patients.

Hua R, Hua F, Jiao Y, Pan Y, Yang X, Peng S, Niu J.

Am J Transl Res. 2016;8(6):2851-61.

PubMed [citation]

PMID:: 27398169
PMCID:: PMC4931180

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV003447403.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 250 of the ATP7B protein (p.Gly250Arg). This variant is present in population databases (rs192444554, gnomAD 0.05%). This missense change has been observed in individual(s) with Wilson disease (PMID: 27398169, 34470610). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 All of Us Research Program, National Institutes of Health, SCV004829380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces glycine with arginine at codon 250 of the ATP7B protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 27398169, 30702195, 34470610, 36253962). One of these individuals also carried a pathogenic variant in unknown phase (PMID: 27398169). This variant has been identified in 10/280418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: May 7, 2024

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