VCV000554444.21 - ClinVar

NM_000053.4(ATP7B):c.2549C>T (p.Thr850Ile)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000053.4(ATP7B):c.2549C>T (p.Thr850Ile)

Variation ID: 554444 Accession: VCV000554444.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.3 13: 51950298 (GRCh38) [ NCBI UCSC ] 13: 52524434 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Feb 25, 2025	Apr 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000053.4:c.2549C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000044.2:p.Thr850Ile	missense
NM_001005918.3:c.2063C>T	NP_001005918.1:p.Thr688Ile	missense
NM_001243182.2:c.2216C>T	NP_001230111.1:p.Thr739Ile	missense
NM_001330578.2:c.2315C>T	NP_001317507.1:p.Thr772Ile	missense
NM_001330579.2:c.2297C>T	NP_001317508.1:p.Thr766Ile	missense
NC_000013.11:g.51950298G>A
NC_000013.10:g.52524434G>A
NG_008806.1:g.66197C>T

... more HGVS ... less HGVS

Protein change

T850I, T766I, T772I, T739I, T688I

Other names

Canonical SPDI

NC_000013.11:51950297:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA6988979 dbSNP: rs777629392 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATP7B		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	3212	3360

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Wilson disease	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 25, 2024	RCV000670079.14
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 21, 2022	RCV001509442.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Oct 18, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794895.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 25089800‚ 27398169‚ 21034864

Likely pathogenic (Oct 21, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001716164.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (6) PubMed: 21034864‚ 25089800‚ 27398169‚ 27706781‚ 29321352‚ 30702195 Comment: PP3, PP4, PM2, PS4_moderate Number of individuals with the variant: 2

Pathogenic (Apr 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV002799405.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025

Pathogenic (Dec 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001201648.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 21034864‚ 27398169‚ 29321352 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 850 of the ATP7B protein (p.Thr850Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 850 of the ATP7B protein (p.Thr850Ile). This variant is present in population databases (rs777629392, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21034864, 27398169, 29321352). ClinVar contains an entry for this variant (Variation ID: 554444). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)

Likely pathogenic (Jan 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilson disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004216408.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Pathogenic (Jun 28, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Wilson disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002087843.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 850 of the ATP7B protein (p.Thr850Ile). This variant is present in population databases (rs777629392, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21034864, 27398169, 29321352). ClinVar contains an entry for this variant (Variation ID: 554444). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants.	Li X	Human mutation	2019	PMID: 30702195
Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B.	Tuan Pham LA	Journal of genetics	2017	PMID: 29321352
Direct sequencing of mutations in the copper-transporting P-type adenosine triphosphate (ATP7B) gene for diagnosis and pathogenesis of Wilson's disease.	Zhang DF	Genetics and molecular research : GMR	2016	PMID: 27706781
Mutational analysis of ATP7B in Chinese Wilson disease patients.	Hua R	American journal of translational research	2016	PMID: 27398169
Mutational characterization of ATP7B gene in 103 Wilson's disease patients from Southern China: identification of three novel mutations.	Wei Z	Neuroreport	2014	PMID: 25089800
Six novel ATP7B mutations in Thai patients with Wilson disease.	Panichareon B	European journal of medical genetics	2011	PMID: 21034864

Text-mined citations for rs777629392 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000053.4(ATP7B):c.2549C>T (p.Thr850Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777629392 ...