The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease (Dedoussis 2005, Gu 2013, Panagiotakaki 2004, Yu 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 37122), and is found in the East Asian population with an allele frequency of 0.041% (8/19,538 alleles) in the Genome Aggregation Database. The isoleucine at codon 1148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ile1148Thr variant is considered to be pathogenic. References: Dedoussis GV et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34.
ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr)
Germline
Classification
Help
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.
(17)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
17
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr)
Variation ID: 37122 Accession: VCV000037122.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q14.3 13: 51941194 (GRCh38) [ NCBI UCSC ] 13: 52515330 (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 Mar 29, 2015 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000053.4:c.3443T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Ile1148Thr missense NM_001005918.3:c.2822T>C NP_001005918.1:p.Ile941Thr missense NM_001243182.2:c.3110T>C NP_001230111.1:p.Ile1037Thr missense NM_001330578.2:c.3209T>C NP_001317507.1:p.Ile1070Thr missense NM_001330579.2:c.3191T>C NP_001317508.1:p.Ile1064Thr missense NC_000013.11:g.51941194A>G NC_000013.10:g.52515330A>G NG_008806.1:g.75301C>T NG_008806.1:g.75301T>C P35670:p.Ile1148Thr - Protein change
- I1148T, I1037T, I1070T, I1064T, I941T
- Other names
- -
- Canonical SPDI
- NC_000013.11:51941193:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| ATP7B | - | - |
GRCh38 GRCh37 |
2915 | 3059 | |
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. |
|---|---|---|---|---|
| Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2024 | RCV000023582.42 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000727509.23 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 24, 2015 | RCV002453275.9 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Nov 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158017.1
First in ClinVar: Feb 09, 2020 Last updated: Feb 09, 2020 |
Comment:
The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease … (more)
The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease (Dedoussis 2005, Gu 2013, Panagiotakaki 2004, Yu 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 37122), and is found in the East Asian population with an allele frequency of 0.041% (8/19,538 alleles) in the Genome Aggregation Database. The isoleucine at codon 1148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ile1148Thr variant is considered to be pathogenic. References: Dedoussis GV et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. (less)
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|
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Pathogenic
(Jan 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021340.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216283.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916630.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). … (more)
Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277638 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.3443T>C, has been reported in the literature in multiple individuals affected with Wilson Disease, in trans with other pathogenic variants (Loudianos_1998, Haas_1999, Gu_2003, Abdelghaffar_2008, Mak_2008, Panagiotakaki_2004). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Luoma_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001977254.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201455.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Reported as a founder variant among individuals of Chinese background (PMID: 18034201, 23518715, 23843956, 25089800); Published functional studies suggest a moderate loss of function for … (more)
Reported as a founder variant among individuals of Chinese background (PMID: 18034201, 23518715, 23843956, 25089800); Published functional studies suggest a moderate loss of function for the p.(I1148T) variant (PMID: 20333758); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30366773, 28212618, 34400371, 23843956, 23518715, 21219664, 27398169, 30655162, 30275481, 33763395, 34240825, 35314707, 35470480, 35385937, 35782615, 30884209, 9801873, 18371106, 15967699, 14986826, 36253962, 35222532, 30384382, 18760268, 31172689, 24475083, 34470610, 26112727, 33668890, 28433102, 18034201, 20333758, 22692182, 25089800, 27982432, 15845031, 34002136, 27022412, 15523622, 36096368, 29930488, 26580967, 35538921, 10447265, 21034864, 18483695, 34324271, 21796144, 35444691) (less)
|
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Pathogenic
(Jun 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000709306.2
First in ClinVar: Oct 21, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Likely pathogenic
(Apr 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002525815.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
PS3, PM2, PP3
|
|
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Pathogenic
(Jun 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183370.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS4, PM2, PM3, PP1
Geographic origin: Brazil
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000942645.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1148 of the ATP7B protein (p.Ile1148Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1148 of the ATP7B protein (p.Ile1148Thr). This variant is present in population databases (rs60431989, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 23843956, 28212618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37122). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847801.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ile1148Thr variant in ATP7B has been reported in >10 individuals with Wilson disease, including at least 2 homozygotes and 8 compound heterozygotes (Gu 2013 … (more)
The p.Ile1148Thr variant in ATP7B has been reported in >10 individuals with Wilson disease, including at least 2 homozygotes and 8 compound heterozygotes (Gu 2013 PMID: 23843956, Hua 2016 PMID: 27398169, Manolaki 2009 PMID: 19172127, Yu 2017 PMID: 28212618). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 37122) and has been identified in 0.02% (1/3472) of Ashkenazi Jewish and 0.005% (2/41438) chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is low enough to be consistent with a recessive allele frequency for Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3. (less)
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Likely pathogenic
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002614689.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide … (more)
The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3443. The isoleucine at codon 1148 is replaced by threonine, an amino acid with similar properties. In two studies, this alteration was detected in cohorts of individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) at rates of 8.7% and 9% (Mak CM, et al. J. Hum. Genet. 2008 ; 53(1):55-63, Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5). In one functional study, authors showed that this alteration did not show a loss of expression of full length protein on western blot, but they explained that the alteration is present in a b-sheet, with its functional group facing toward the nucleotide binding pocket, and may therefore affect hydrophobicity (Luoma LM, et al. Hum. Mutat. 2010;31(5):569-77). This alteration has been detected in both the heterozygous and homozygous state in several chromosomes from individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) (Gu S, et al. PLoS ONE 2013;8(7):e66526, Loudianos G, et al. Eur. J. Hum. Genet.;6(5):487-91, Dedoussis GV, et al. Ann. Hum. Genet. 2005;69(Pt 3):268-74, Panagiotakaki E, et al. Am. J. Med. Genet. A 2004;131(2):168-73, Vrabelova S, et al. Mol. Genet. Metab. ; 86(1-2):277-85, Panichareon B, et al. Eur J Med Genet ; 54(2):103-7). This variant was previously reported in the SNPDatabase as rs60431989, but was not reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP) population-based cohorts. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
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Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004811232.7
First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024 |
Comment:
ATP7B: PM3:Very Strong, PM2, PP4, PS3:Supporting
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004845359.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces isoleucine with threonine at codon 1148 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces isoleucine with threonine at codon 1148 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant results in normal protein expression and mild to intermediate deficits in a complementation assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 9801873, 10447265, 14986826, 15523622, 15845031, 17587212, 18034201, 18483695, 21796144, 21034864, 22677543, 24146181, 23843956, 23275100, 25089800, 24726229, 26580967, 27022412, 27982432, 28212618, 29930488, 30384382, 30884209, 30702195, 34470610, 34400371, 35782615) and is consider a founder variant in several Chinese populations (PMID: 23843956, 30384382). In a number of these individuals, this variant was confirmed to be in the homozygous state or compound heterozygous state (PMID: 15523622, 20465995, 24146181, 23843956, 23275100, 27982432, 28212618, 30702195). One individual carried this variant along with a variant of uncertain significance in cis and third variant known to be pathogenic in trans (PMID: 15845031). In a separate study, this variant was identified in four individuals affected with Wilson disease, all carrying the same variant of uncertain significance in cis and different known pathogenic variants in trans (PMID: 18034201). This variant has been identified in 11/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 2
|
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Pathogenic
(Sep 01, 2011)
|
no assertion criteria provided
Method: literature only
|
WILSON DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044873.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 29, 2020 |
Comment on evidence:
In Chinese patients with Wilson disease (WND; 277900), Wang et al. (2011) identified a 3443T-C transition in exon 16 of the ATP7B gene, resulting in … (more)
In Chinese patients with Wilson disease (WND; 277900), Wang et al. (2011) identified a 3443T-C transition in exon 16 of the ATP7B gene, resulting in an ile1148-to-thr (I1148T) substitution in the ATP loop of the protein. The I1148T mutation was the second most common mutation among 69 Chinese patients with Wilson disease, accounting for 9.59% of mutant alleles. (less)
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455588.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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Pathogenic
(Feb 27, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220681.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Comment:
Comment:
Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277638 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.3443T>C, has been reported in the literature in multiple individuals affected with Wilson Disease, in trans with other pathogenic variants (Loudianos_1998, Haas_1999, Gu_2003, Abdelghaffar_2008, Mak_2008, Panagiotakaki_2004). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Luoma_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Reported as a founder variant among individuals of Chinese background (PMID: 18034201, 23518715, 23843956, 25089800); Published functional studies suggest a moderate loss of function for the p.(I1148T) variant (PMID: 20333758); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30366773, 28212618, 34400371, 23843956, 23518715, 21219664, 27398169, 30655162, 30275481, 33763395, 34240825, 35314707, 35470480, 35385937, 35782615, 30884209, 9801873, 18371106, 15967699, 14986826, 36253962, 35222532, 30384382, 18760268, 31172689, 24475083, 34470610, 26112727, 33668890, 28433102, 18034201, 20333758, 22692182, 25089800, 27982432, 15845031, 34002136, 27022412, 15523622, 36096368, 29930488, 26580967, 35538921, 10447265, 21034864, 18483695, 34324271, 21796144, 35444691)
Comment:
PS3, PM2, PP3
Comment:
ACMG classification criteria: PS4, PM2, PM3, PP1
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1148 of the ATP7B protein (p.Ile1148Thr). This variant is present in population databases (rs60431989, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 23843956, 28212618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37122). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Ile1148Thr variant in ATP7B has been reported in >10 individuals with Wilson disease, including at least 2 homozygotes and 8 compound heterozygotes (Gu 2013 PMID: 23843956, Hua 2016 PMID: 27398169, Manolaki 2009 PMID: 19172127, Yu 2017 PMID: 28212618). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 37122) and has been identified in 0.02% (1/3472) of Ashkenazi Jewish and 0.005% (2/41438) chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is low enough to be consistent with a recessive allele frequency for Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3.
Comment:
The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3443. The isoleucine at codon 1148 is replaced by threonine, an amino acid with similar properties. In two studies, this alteration was detected in cohorts of individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) at rates of 8.7% and 9% (Mak CM, et al. J. Hum. Genet. 2008 ; 53(1):55-63, Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5). In one functional study, authors showed that this alteration did not show a loss of expression of full length protein on western blot, but they explained that the alteration is present in a b-sheet, with its functional group facing toward the nucleotide binding pocket, and may therefore affect hydrophobicity (Luoma LM, et al. Hum. Mutat. 2010;31(5):569-77). This alteration has been detected in both the heterozygous and homozygous state in several chromosomes from individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) (Gu S, et al. PLoS ONE 2013;8(7):e66526, Loudianos G, et al. Eur. J. Hum. Genet.;6(5):487-91, Dedoussis GV, et al. Ann. Hum. Genet. 2005;69(Pt 3):268-74, Panagiotakaki E, et al. Am. J. Med. Genet. A 2004;131(2):168-73, Vrabelova S, et al. Mol. Genet. Metab. ; 86(1-2):277-85, Panichareon B, et al. Eur J Med Genet ; 54(2):103-7). This variant was previously reported in the SNPDatabase as rs60431989, but was not reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP) population-based cohorts. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
ATP7B: PM3:Very Strong, PM2, PP4, PS3:Supporting
Comment:
This missense variant replaces isoleucine with threonine at codon 1148 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant results in normal protein expression and mild to intermediate deficits in a complementation assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 9801873, 10447265, 14986826, 15523622, 15845031, 17587212, 18034201, 18483695, 21796144, 21034864, 22677543, 24146181, 23843956, 23275100, 25089800, 24726229, 26580967, 27022412, 27982432, 28212618, 29930488, 30384382, 30884209, 30702195, 34470610, 34400371, 35782615) and is consider a founder variant in several Chinese populations (PMID: 23843956, 30384382). In a number of these individuals, this variant was confirmed to be in the homozygous state or compound heterozygous state (PMID: 15523622, 20465995, 24146181, 23843956, 23275100, 27982432, 28212618, 30702195). One individual carried this variant along with a variant of uncertain significance in cis and third variant known to be pathogenic in trans (PMID: 15845031). In a separate study, this variant was identified in four individuals affected with Wilson disease, all carrying the same variant of uncertain significance in cis and different known pathogenic variants in trans (PMID: 18034201). This variant has been identified in 11/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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:
The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease (Dedoussis 2005, Gu 2013, Panagiotakaki 2004, Yu 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 37122), and is found in the East Asian population with an allele frequency of 0.041% (8/19,538 alleles) in the Genome Aggregation Database. The isoleucine at codon 1148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ile1148Thr variant is considered to be pathogenic. References: Dedoussis GV et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34.
Comment:
Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277638 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.3443T>C, has been reported in the literature in multiple individuals affected with Wilson Disease, in trans with other pathogenic variants (Loudianos_1998, Haas_1999, Gu_2003, Abdelghaffar_2008, Mak_2008, Panagiotakaki_2004). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Luoma_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Reported as a founder variant among individuals of Chinese background (PMID: 18034201, 23518715, 23843956, 25089800); Published functional studies suggest a moderate loss of function for the p.(I1148T) variant (PMID: 20333758); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30366773, 28212618, 34400371, 23843956, 23518715, 21219664, 27398169, 30655162, 30275481, 33763395, 34240825, 35314707, 35470480, 35385937, 35782615, 30884209, 9801873, 18371106, 15967699, 14986826, 36253962, 35222532, 30384382, 18760268, 31172689, 24475083, 34470610, 26112727, 33668890, 28433102, 18034201, 20333758, 22692182, 25089800, 27982432, 15845031, 34002136, 27022412, 15523622, 36096368, 29930488, 26580967, 35538921, 10447265, 21034864, 18483695, 34324271, 21796144, 35444691)
Comment:
PS3, PM2, PP3
Comment:
ACMG classification criteria: PS4, PM2, PM3, PP1
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1148 of the ATP7B protein (p.Ile1148Thr). This variant is present in population databases (rs60431989, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 23843956, 28212618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37122). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Ile1148Thr variant in ATP7B has been reported in >10 individuals with Wilson disease, including at least 2 homozygotes and 8 compound heterozygotes (Gu 2013 PMID: 23843956, Hua 2016 PMID: 27398169, Manolaki 2009 PMID: 19172127, Yu 2017 PMID: 28212618). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 37122) and has been identified in 0.02% (1/3472) of Ashkenazi Jewish and 0.005% (2/41438) chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is low enough to be consistent with a recessive allele frequency for Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3.
Comment:
The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3443. The isoleucine at codon 1148 is replaced by threonine, an amino acid with similar properties. In two studies, this alteration was detected in cohorts of individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) at rates of 8.7% and 9% (Mak CM, et al. J. Hum. Genet. 2008 ; 53(1):55-63, Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5). In one functional study, authors showed that this alteration did not show a loss of expression of full length protein on western blot, but they explained that the alteration is present in a b-sheet, with its functional group facing toward the nucleotide binding pocket, and may therefore affect hydrophobicity (Luoma LM, et al. Hum. Mutat. 2010;31(5):569-77). This alteration has been detected in both the heterozygous and homozygous state in several chromosomes from individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) (Gu S, et al. PLoS ONE 2013;8(7):e66526, Loudianos G, et al. Eur. J. Hum. Genet.;6(5):487-91, Dedoussis GV, et al. Ann. Hum. Genet. 2005;69(Pt 3):268-74, Panagiotakaki E, et al. Am. J. Med. Genet. A 2004;131(2):168-73, Vrabelova S, et al. Mol. Genet. Metab. ; 86(1-2):277-85, Panichareon B, et al. Eur J Med Genet ; 54(2):103-7). This variant was previously reported in the SNPDatabase as rs60431989, but was not reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP) population-based cohorts. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
ATP7B: PM3:Very Strong, PM2, PP4, PS3:Supporting
Comment:
This missense variant replaces isoleucine with threonine at codon 1148 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant results in normal protein expression and mild to intermediate deficits in a complementation assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 9801873, 10447265, 14986826, 15523622, 15845031, 17587212, 18034201, 18483695, 21796144, 21034864, 22677543, 24146181, 23843956, 23275100, 25089800, 24726229, 26580967, 27022412, 27982432, 28212618, 29930488, 30384382, 30884209, 30702195, 34470610, 34400371, 35782615) and is consider a founder variant in several Chinese populations (PMID: 23843956, 30384382). In a number of these individuals, this variant was confirmed to be in the homozygous state or compound heterozygous state (PMID: 15523622, 20465995, 24146181, 23843956, 23275100, 27982432, 28212618, 30702195). One individual carried this variant along with a variant of uncertain significance in cis and third variant known to be pathogenic in trans (PMID: 15845031). In a separate study, this variant was identified in four individuals affected with Wilson disease, all carrying the same variant of uncertain significance in cis and different known pathogenic variants in trans (PMID: 18034201). This variant has been identified in 11/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation spectrum of ATP7B gene in pediatric patients with Wilson disease in Vietnam. | Huong NTM | Molecular genetics and metabolism reports | 2022 | PMID: 35782615 |
| Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. | Li M | BMC gastroenterology | 2021 | PMID: 34470610 |
| ATP7B variant spectrum in a French pediatric Wilson disease cohort. | Couchonnal E | European journal of medical genetics | 2021 | PMID: 34400371 |
| Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. | Qian Z | Molecular genetics & genomic medicine | 2019 | PMID: 30884209 |
| 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 |
| Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease. | Xiao H | Digestion | 2019 | PMID: 30384382 |
| Multiplex Ligation-dependent Probe Amplification Analysis Subsequent to Direct DNA Full Sequencing for Identifying ATP7B Mutations and Phenotype Correlations in Children with Wilson Disease. | Shim JO | Journal of Korean medical science | 2018 | PMID: 29930488 |
| Clinical features and outcome in patients with osseomuscular type of Wilson's disease. | Yu H | BMC neurology | 2017 | PMID: 28212618 |
| Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease. | Cheng N | Clinical genetics | 2017 | PMID: 27982432 |
| Mutational analysis of ATP7B in Chinese Wilson disease patients. | Hua R | American journal of translational research | 2016 | PMID: 27398169 |
| Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. | Dong Y | Theranostics | 2016 | PMID: 27022412 |
| Multi-allele genotyping platform for the simultaneous detection of mutations in the Wilson disease related ATP7B gene. | Amvrosiadou M | Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | 2015 | PMID: 26580967 |
| 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 |
| Delayed appearance of wing-beating tremor after liver transplantation in a patient with Wilson disease. | Kim JS | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2014 | PMID: 24726229 |
| Isolated persistent elevation of alanine transaminase for early diagnosis of pre-symptomatic Wilson's disease in Chinese children. | Hui J | World journal of pediatrics : WJP | 2013 | PMID: 24146181 |
| Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. | Gu S | PloS one | 2013 | PMID: 23843956 |
| Identification of one novel and nine recurrent mutations of the ATP7B gene in 11 children with Wilson disease. | Geng J | World journal of pediatrics : WJP | 2013 | PMID: 23275100 |
| Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. | Bost M | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2012 | PMID: 22677543 |
| Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. | Wang LH | Journal of human genetics | 2011 | PMID: 21796144 |
| Six novel ATP7B mutations in Thai patients with Wilson disease. | Panichareon B | European journal of medical genetics | 2011 | PMID: 21034864 |
| Development of a high-resolution melting method for the screening of Wilson disease-related ATP7B gene mutations. | Lin CW | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20465995 |
| Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. | Luoma LM | Human mutation | 2010 | PMID: 20333758 |
| Wilson disease in children: analysis of 57 cases. | Manolaki N | Journal of pediatric gastroenterology and nutrition | 2009 | PMID: 19172127 |
| Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. | Abdelghaffar TY | Journal of human genetics | 2008 | PMID: 18483695 |
| Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease. | Gojová L | Clinical genetics | 2008 | PMID: 18371106 |
| Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. | Mak CM | Journal of human genetics | 2008 | PMID: 18034201 |
| Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. | Park S | Human mutation | 2007 | PMID: 17587212 |
| Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. | Vrabelova S | Molecular genetics and metabolism | 2005 | PMID: 15967699 |
| Wilson disease: high prevalence in a mountainous area of Crete. | Dedoussis GV | Annals of human genetics | 2005 | PMID: 15845031 |
| Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). | Panagiotakaki E | American journal of medical genetics. Part A | 2004 | PMID: 15523622 |
| Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. | Gu YH | Clinical genetics | 2003 | PMID: 14986826 |
| Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online. | Haas R | Human mutation | 1999 | PMID: 10447265 |
| Haplotype and mutation analysis in Greek patients with Wilson disease. | Loudianos G | European journal of human genetics : EJHG | 1998 | PMID: 9801873 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B | - | - | - | - |
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Text-mined citations for rs60431989 ...
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Record last updated Oct 27, 2024
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