NM_000053.4:c.2332C>G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2332C>G(p.Arg778Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,890 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R778L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 1.89

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity ATP7B_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-51958333-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 13-51958334-G-C is Pathogenic according to our data. Variant chr13-51958334-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156283.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.2332C>G	p.Arg778Gly	missense_variant	Exon 8 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.2332C>G	p.Arg778Gly	missense_variant	Exon 8 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249436

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135340

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727246

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:10Other:1

Feb 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 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 arginine with glycine at codon 778 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). Although functional studies have not been reported for this variant, it alters a conserved arginine residue in the transmembrane M2 domain of the ATP7B protein (a.a. 764 - 784), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in many individuals affected with Wilson disease (PMID: 8533760, 9801873, 11216666, 12515040, 16207219, 16283883, 16998622, 17154398, 17272994, 18371106, 20517649, 20958917, 21406212, 21682854, 22093921, 22677543, 23333878, 23518715, 24517292, 26215059, 27935710, 30230192, 31708252, 33159804, 34400371). In a number of these individuals, this variant was reported in the compound heterozygous state or the homozygous state (PMID: 16283883, 17272994, 20517649, 22093921, 23518715, 24517292). Different missense variants occurring at the same codon, p.Arg778Leu, p.Arg778Trp, and p.Arg778Gln, are known to cause disease (ClinVar variation ID: 3852, 456553, 550914), indicating that arginine at this position is important for ATP7B protein function. This variant has been identified in 2/249436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 778 of the ATP7B protein (p.Arg778Gly). This variant is present in population databases (rs137853284, gnomAD 0.002%). This missense change has been observed in individual(s) with Wilson disease (PMID: 20517649, 21682854, 23333878). ClinVar contains an entry for this variant (Variation ID: 156283). 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%. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11243728, 11479773, 16998622, 17160357, 23518715). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 21, 2019

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.2332C>G (p.Arg778Gly) results in a non-conservative amino acid change in the encoded protein sequence. 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 8.1e-06 in 246100 control chromosomes (gnomAD). c.2332C>G has been reported in the literature in multiple individuals affected with Wilson Disease (Ferenci_2014). These data indicate that the variant is very likely to be associated with disease. In addition, another variant, c.2332C>T (p.Arg778Trp) affecting the same codon has been classified as pathogenic, therefore, suggesting the importance of this location for ATP7B protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 23, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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.Arg778Gly variant in ATP7B has been reported in several individuals with Wilson disease, including at least 4 homozygous and 3 compound heterozygous individuals (AbdelGhaffar 2011, Bruha 2011, Coffey 2013, Figus 1995, Gromadzka 2005, Petrasek 2007, Simsek Papur 2013, Vrabelova 2005, Weiss 2010). It has also been identified in 0.001% (2/113168) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a pathogenic variant at the same position, p.Arg778Trp, has also been reported in many individuals with Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_Strong, PM2, PM5, PP3, PP4. -

not provided

Pathogenic:2

Apr 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 17272994, 8533760, 34400371, 24253677, 22692182, 9801873, 11216666, 16207219, 31708252, 32043565, 34426522, 33098801, 35872528, 33159804, 16283883) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM3:Very Strong, PM1, PM2, PM5, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.6

D;D;.;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;B;D;D

Vest4

0.98

MutPred

0.92

Loss of MoRF binding (P = 0.0457);.;.;Loss of MoRF binding (P = 0.0457);

MVP

0.98

MPC

0.42

ClinPred

0.99

GERP RS

3.5

Varity_R

0.95

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over