rs60431989

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.3443T>C(p.Ile1148Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.27

Publications

51 publications found

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

Wilson disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000053.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 13-51941194-A-G is Pathogenic according to our data. Variant chr13-51941194-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.3443T>C	p.Ile1148Thr	missense_variant	Exon 16 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.3443T>C	p.Ile1148Thr	missense_variant	Exon 16 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

249586

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000389

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112008

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000956

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:13

Aug 10, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 27, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 13, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr) variant results in a missense substitution of isoleucine with threonine at codon 1148, altering a highly conserved nucleotide within the N-domain of the ATP7B protein (amino acids 1032–1196), a region critical for its function (PMID: 35245129). This variant is extremely rare in the general population, with a frequency of 0.0000192 in gnomAD, and no homozygous individuals observed. Functional studies in yeast models demonstrated normal protein expression but mild to intermediate impairment in copper transport complementation assays (PMID: 20333758).The variant is reported as Pathogenic/Likely Pathogenic in ClinVar (Variation ID: 37122) and has been identified in numerous individuals diagnosed with Wilson disease across multiple studies. -

Jun 23, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM2, PM3, PP1 -

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Sep 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 09, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 10, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This variant alters a conserved isoleucine residue in the N domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). 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. -

Jan 08, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:4

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATP7B: PM3:Very Strong, PM2, PP4, PS3:Supporting -

Jun 20, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM2, PP3 -

Oct 31, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Inborn genetic diseases

Pathogenic:1

Nov 24, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;.;.;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;.;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D;D;D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D;D

Vest4

0.89

MutPred

0.89

Loss of stability (P = 0.002);.;.;.;.;.;.;

MVP

0.97

MPC

0.42

ClinPred

0.86

GERP RS

5.0

Varity_R

0.92

gMVP

0.74

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over