NM_000053.4(ATP7B):c.1297A>G (p.Thr433Ala) AND Wilson disease

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV001066306.6

Allele description [Variation Report for NM_000053.4(ATP7B):c.1297A>G (p.Thr433Ala)]

NM_000053.4(ATP7B):c.1297A>G (p.Thr433Ala)

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.1297A>G (p.Thr433Ala)

HGVS:

NC_000013.11:g.51970738T>C
NG_008806.1:g.45757A>G
NM_000053.4:c.1297A>GMANE SELECT
NM_001005918.3:c.1297A>G
NM_001243182.2:c.964A>G
NM_001330578.2:c.1297A>G
NM_001330579.2:c.1297A>G
NP_000044.2:p.Thr433Ala
NP_001005918.1:p.Thr433Ala
NP_001230111.1:p.Thr322Ala
NP_001317507.1:p.Thr433Ala
NP_001317508.1:p.Thr433Ala
NC_000013.10:g.52544874T>C
NC_000013.10:g.52544874T>C
NM_000053.3:c.1297A>G

Protein change:

T322A

Links:

dbSNP: rs532864884

NCBI 1000 Genomes Browser:

rs532864884

Molecular consequence:

NM_000053.4:c.1297A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.1297A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.964A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.1297A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.1297A>G - 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
SCV001231313	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001456189	Natera, Inc.	no assertion criteria provided	Uncertain significance (Mar 17, 2020)	germline	clinical testing
SCV002793210	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 26, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004829413	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	9	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV001231313.2

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 433 of the ATP7B protein (p.Thr433Ala). This variant is present in population databases (rs532864884, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 860062). 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 Natera, Inc., SCV001456189.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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 Fulgent Genetics, Fulgent Genetics, SCV002793210.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV004829413.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces threonine with alanine at codon 433 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 not been reported in individuals affected with ATP7B-related disorders in the literature. This variant has been identified in 13/279776 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		9	not provided	not provided	not provided

Last Updated: May 7, 2024

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