rs764131178

Variant names:

• chr13-51944170-C-T
• rs764131178
• NM_000053.4:c.3182G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3182G>A​(p.Gly1061Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,874 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1061R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 4.98
• Publications: 23 publications found

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)

ACMG classification

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

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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, 0.967
• PP5: Variant 13-51944170-C-T is Pathogenic according to our data. Variant chr13-51944170-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 312383.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	c.3182G>A	p.Gly1061Glu	missense_variant	Exon 14 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3182G>A	p.Gly1061Glu	missense_variant	Exon 14 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249320 AF XY: 0.0000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000156 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000496 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:12

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2021

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 14 of the ATP7B gene that results in the amino acid substitution of Glutamic acid for Glycine at codon 1061 was detected. The observed variation c.3182G>A (p.Gly1061Glu) lies in the haloacid dehalogenase-like hydrolase domain of the ATP7B protein and has previously been reported in patients affected with Wilson disease [Roy et al. 2020]. The functional studies showed that this variation causes ATP7B retention in the endoplasmic reticulum, inhibits Cu-transport, and lowers ATP7B protein abundance [Roy et al. 2020]. The variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in silico predictions of the variant is probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

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CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly1061Glu variant has been reported in many individuals with Wilson disease, including at least 3 homozygotes and 7 compound heterozygotes (Curtis 1999, Guggilla 2015, Gupta 2007, Loudianos 1999, Margarit 2005, Santhosh 2006). This variant was identified in 0.03% (12/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough frequency to be consistent with a recessive allele. 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, PP4. -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000312383, PMID:10502777). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 10544227). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:30655162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.928>=0.6, 3CNET: 0.933>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000481). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.3182G>A (p.Gly1061Glu) missense variant has been well-documented as a pathogenic variant for Wilson disease in many different populations. Across a selection of available literature, the p.Gly1061Glu variant has been identified in a homozygous state in seven patients, in a compound heterozygous state in six patients, and in a heterozygous state in four patients in whom a second variant was not identified (Curtis et al. 1999; Loudianos et al. 1999; Margarit et al. 2005; Santhosh et al. 2006; Khan et al. 2012; Guggilla et al. 2015). Gupta et al. (2007) also found the p.Gly1061Glu variant on 11% of Wilson disease patient chromosomes in the Indian population. The p.Gly1061Glu variant was absent from 222 controls and is reported at a frequency of 0.00036 in the South Asian population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Gly1061Glu variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 25, 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 glycine with glutamic acid at codon 1061 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). This variant occurs in the functionally important ATP nucleotide-binding (N) domain (a.a. 1032 - 1196) that mediates the generation of energy need to transport copper (PMID: 35245129). A functional study showed that the variant resulted in ATP7B retention in the endoplasmic reticulum, inhibition of copper transport, and lower ATP7B protein expression compared to wild-type (PMID: 32778786). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 11216666, 10544227, 15024742, 15523622, 15952988, 17264425, 17634212, 17823867, 19172127, 20517649, 20967755, 23518715, 24094725, 25982861, 27982432, 30120852, 31059521, 34002136, 35535059), including in the homozygous state with no evidence of consanguinity (PMID: 10502777, 15952988, 20517649, 23518715, 31059521) and in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 10544227, 15024742, 15952988, 17823867, 20967755, 23518715, 30120852, 34002136, 35535059). This variant has been identified in 12/249320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.3182G>A(p.Gly1061Glu) in ATP7B gene has been reported previously in homozygous and compound heterozygous state in multiple individual(s) with Wilson disease. This mutation is one of three common mutations often found in individuals with Wilson disease from South and East India, but has also been reported in affected individuals from other regions (Gupta A, et al., 2007; Guggilla SR, et al., 2015; Singh N, et al.,2019). The G1061E mutations, which are located within the ATPbinding domain, cause ATP7B retention in the endoplasmic reticulum, inhibit Cu-transport, and lower ATP7B protein abundance (Roy S, et al., 2020). This variant is reported with the allele frequency 0.005% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Glycine at position 1061 is changed to a Glutamic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1061 of the ATP7B protein (p.Gly1061Glu). This variant is present in population databases (rs764131178, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 10544227, 15024742, 17264425, 17823867). ClinVar contains an entry for this variant (Variation ID: 312383). 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. -

not provided Pathogenic:2

Jun 24, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3, PM1, PM2, PP3, PP4 -

Apr 16, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Found on 11% of Wilson disease patient chromosomes in the Indian population (Gupta et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10502777, 22692182, 25982861, 33083013, 31589614, 24094725, 23430908, 18371106, 26207595, 17634212, 25900946, 17823867, 17264425, 15952988, 30120852, 15024742, 10544227) -

not specified Pathogenic:1

Jan 12, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 27, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1061E pathogenic mutation (also known as c.3182G>A), located in coding exon 14 of the ATP7B gene, results from a G to A substitution at nucleotide position 3182. The glycine at codon 1061 is replaced by glutamic acid, an amino acid with similar properties. This mutation is one of three common mutations often found in individuals with Wilson disease from South and East India, but has also been reported in affected individuals from other regions (Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Guggilla SR et al. Gene, 2015 Sep;569:83-7). This mutation has been identified in multiple homozygous and compound heterozygous individuals with Wilson disease (Curtis D et al. Hum. Mutat., 1999;14:304-11; Margarit E et al. Clin. Genet., 2005 Jul;68:61-8; Santhosh S et al. Indian J Gastroenterol, 2006;25:277-82; Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Mukherjee S et al. Parkinsonism Relat. Disord., 2014 Jan;20:75-81; Guggilla SR et al. Gene, 2015 Sep;569:83-7). Another study, in which authors modeled the structural effects of various mutations on the ATP7B gene, showed that this mutation site is sensitive to substitutions (Schushan M et al. Metallomics, 2012 Jul;4:669-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D;.;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;B;D;D;D
Vest4		0.98
MVP		1.0
MPC		0.42
ClinPred		0.69	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs764131178; hg19: chr13-52518306;