rs764131178

chr13-51944170-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G1061G) has been classified as Likely benign.

• 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:15
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 312383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51944170-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3182G>A	p.Gly1061Glu	missense_variant	14/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3182G>A	p.Gly1061Glu	missense_variant	14/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000481 AC: 12 AN: 249320 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135342

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000364 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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G1061E in ATP7B (NM_000053.3) has been reported previously in multiple patients (Gupta A et al; Santhosh S et al; Guggilla et al). It is a common variant in the Indian population. The p.G1061E variant is observed in 12/30,602 (0.0392%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The p.G1061E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1061 of ATP7B is conserved in all mammalian species. The nucleotide c.3182 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 07, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2021	PS4, PS3, PM1, PM2, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	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

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 12, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2017

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;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs764131178; hg19: chr13-52518306;