chr13-51961906-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.1877G>C(p.Gly626Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,613,478 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G626G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.11

Publications

11 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.

PM2

Very rare variant in population databases, with high coverage;

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, 0.942

PP5

Variant 13-51961906-C-G is Pathogenic according to our data. Variant chr13-51961906-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 157930.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.1877G>C	p.Gly626Ala	missense_variant	Exon 6 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.1877G>C	p.Gly626Ala	missense_variant	Exon 6 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000882

AC:

AN:

249516

AF XY:

0.0000960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1111578

Other (OTH)

AF:

0.0000663

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000789

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000135

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000662

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:11

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with alanine at codon 626 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 have shown conflicting results on the impact of this variant on protein function (PMID: 18203200, 22240481, 24706876). One study showed this variant partially disrupted copper transport but maintained normal phosphorylation activity (PMID: 22240481), while two other studies showed normal copper transport and localization (PMID: 18203200, 24706876). This variant has been reported in many individuals affected with Wilson disease (PMID: 8533760, 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 23518715, 24706876, 26799313, 33640437, 34400371, 36096368). In a number of these individuals, this variant has been determined to be in the compound heterozygous state with another pathogenic variant (PMID: 23518715, 24706876, 26799313, 33640437). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 24/280910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

May 24, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP7B c.1877G>C (p.Gly626Ala) results in a non-conservative amino acid change located in the heavy metal-associated domain, copper ion-binding (IPR006122) of 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 8.8e-05 in 249616 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.1877G>C has been reported in the literature on certain occasions in compound heterozygosity with other pathogenic variants (e.g. p.Gly1061Glu, p.His1069Gln), in multiple individuals affected with Wilson Disease (Bost_2012, Braiterman_2014, Coffey_2013, Figus_1995, Ljubic_2016, Loudianos_1999, Todorov_2005, Collins_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions about the variant effect. Specifically, one study demonstrated the variant to cause partial copper transport activity but normal phosphorylation activity (Huster_2012) while, other studies revealed normal copper transport and trafficking (Braiterman_2014, Hsi_2008). A separate study showed the variant protein retained its ability to interact with COMMD1 but at decreased efficiency (de Bie_2007); however, it is not conclusively established if and how this change could lead to disease. Therefore, these studies do not allow convincing conclusions about the variant effect. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic, n=6; pathogenic, n=1, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Apr 27, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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 29, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

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 alanine, which is neutral and non-polar, at codon 626 of the ATP7B protein (p.Gly626Ala). This variant is present in population databases (rs587783299, gnomAD 0.1%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 24706876, 26799313; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly627Ala. ClinVar contains an entry for this variant (Variation ID: 157930). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 17919502, 18203200, 22240481, 24706876). For these reasons, this variant has been classified as Pathogenic. -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2023

Institute of Genomics, University of Tartu

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This ATP7B c.1877G>C; p.Gly626Ala (rs587783299) variant was identified in the 2020-2023 Wilson's disease genotype-first recall study at the Estonian Biobank. We classified this variant as likely pathogenic according to Richards et al. 2015 ACMG guidelines. Evidence: PM1 (located in the copper ion-binding heavy metal-associated domain (IPR006122)), PM2 (MAF 0.000065 in GnomAD v4.0.0), PM3 (found in trans with another pathogenic variant (p.Met769fs) in our recall study), PP3 (CADD 25.6, Revel 0.89, MutationTester D), PP4 (PMID: 10544227, 23518715; see clinical features), PP5 (SCV000832093.5) -

Aug 10, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Pathogenic:4

Oct 17, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The sequence change, c.1877G>C, is located in exon 6 and results in an amino acid change, p.Gly626Ala. The p.Gly626Ala change affects a highly conserved amino acid residue located in a transmembrane domain of the ATP7B protein. The p.Gly626Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has previously been described in individuals with Wilson disease together with a pathogenic variant (PMIDs: 8533760, 22735241, 8938442, 24706876). Multiple functional studies have shown conflicting results (PMID: 18203200, 22240481, 24706876). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the non-Finnish European subpopulation (dbSNP rs587783299). These collective evidences indicate that this sequence change is likely pathogenic. -

Sep 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4, PM2_moderate, PS4_moderate -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Multiple functional studies have shown conflicting results (Huster D et al., 2012; de Bie P et al., 2007; Hsi G et al., 2008; Braiterman LT et al., 2014; Shah AB et al., 1997; Shanmugavel KP et al., 2019); 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: 23518715, 16207219, 31598802, 31980526, 22735241, 18371106, 9671269, 24798599, 15994426, 10544227, 29063292, 18286826, 22677543, 8938442, 9311736, 8533760, 24706876, 18203200, 17919502, 22240481) -

Inborn genetic diseases

Pathogenic:1

Feb 28, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1877G>C (p.G626A) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a G to C substitution at nucleotide position 1877, causing the glycine (G) at amino acid position 626 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.009% (24/280910) total alleles studied. The highest observed frequency was 0.097% (10/10362) of Ashkenazi Jewish alleles. This alteration was detected in conjunction with another alteration in ATP7B in multiple individuals with Wilson disease (Collins, 2021; Ljubic, 2016; Coffey, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show no significant alterations to copper transport activity in vitro (Hsi, 2008; Huster, 2012; Braiterman, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

ATP7B-related disorder

Pathogenic:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATP7B c.1877G>C variant is predicted to result in the amino acid substitution p.Gly626Ala. This variant has been repeatedly documented to be causative for Wilson Disease (Figus et al. 1995. PubMed ID: 8533760; Loudianos et al. 1999. PubMed ID: 10544227; Shah et al. 1997. PubMed ID: 9311736). This variant is reported in 0.097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;.;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.;.;.;.

PhyloP100

7.1

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.2

D;D;D;.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

D;T;D;.;D

Sift4G

Uncertain

0.023

D;D;D;D;D

Polyphen

1.0

D;D;B;P;D

Vest4

0.94

MVP

1.0

MPC

0.39

ClinPred

0.97

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.87

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

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