13-51941081-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.3556G>A(p.Gly1186Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000558 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. G1186R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 4.96

Publications

20 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 17 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000053.4

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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 13-51941081-C-T is Pathogenic according to our data. Variant chr13-51941081-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188900.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.3556G>A	p.Gly1186Ser	missense_variant, splice_region_variant	Exon 16 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.3556G>A	p.Gly1186Ser	missense_variant, splice_region_variant	Exon 16 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249580

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000259

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14

Jul 24, 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.

Dec 22, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 27, 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 serine, which is neutral and polar, at codon 1186 of the ATP7B protein (p.Gly1186Ser). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs786204547, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson's disease (PMID: 18371106, 20491539, 24010089; 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.G1187S. ClinVar contains an entry for this variant (Variation ID: 188900). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 20491539). For these reasons, this variant has been classified as Pathogenic.

Sep 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.3556G>A; p.Gly1186Ser variant (rs786204547) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease (Couchonnal 2021, Lepori 2012, Park 2007, Tatsumi 2010, Zhang 2022) and has been reported in Wilson disease patients with an additional pathogenic variant (Kim 2013, Okada 2010, Yamaguchi 1998). This variant is also reported in ClinVar (Variation ID: 188900) and is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.868). Additionally, this variant is located at the last nucleotide of exon 16 and computational splicing analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional analysis of patient RNA shows skipping of exon 16 (Okada 2010). Based on available information, this variant is considered to be pathogenic. References: Couchonnal E et al. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet. 2021 Oct;64(10):104305. PMID: 34400371. Kim JW et al. Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases. World J Hepatol. 2013 Mar 27;5(3):156-9. PMID: 23556051. Lepori MB et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 Aug;26(4):147-50. PMID: 22484412. Okada T et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease. Scand J Gastroenterol. 2010 Oct;45(10):1232-7. PMID: 20491539. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13. PMID: 17587212. Tatsumi Y et al. Current state of Wilson disease patients in central Japan. Intern Med. 2010;49(9):809-15. PMID: 20453399. Yamaguchi A et al. Mutations of ATP7B gene in Wilson disease in Japan: identification of nine mutations and lack of clear founder effect in a Japanese population. Hum Mutat. 1998;Suppl 1:S320-2. PMID: 9452121. Zhang S, Yang W, Li X, Pei P, Dong T, Yang Y, Zhang J. Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China. Transl Neurodegener. 2022 Feb 28;11(1):13. PMID: 35220961.

Aug 01, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188900 /PMID: 9452121).Different missense changes at the same codon (p.Gly1186Arg, p.Gly1186Cys, p.Gly1186Val) have been reported to be associated with ATP7B related disorder (PMID: 24094725, 32911910, 9311736). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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.Gly1186Ser (c.3556G>A; also preported as p.G1187S in the literature) variant in ATP7B has been reported in over 6 individuals with Wilson disease, 6 of whom were compound heterozygous for a second ATP7B variant (Okada 2010, Seo 2012, Shimizu 1999, Tatsumi 2010, Vrabelova 2005, Yamaguchi 1998). This variant has been reported in ClinVar (ID 188900) and has also been identified in 0.002% (1/34528) of Latino and 0.0008% (1/113288) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the last base of exon 16 of the ATP7B gene, which is part of the splice consensus sequence. This variant is predicted to result in altered splicing. Furthermore, RT-PCR performed on RNA derived from liver tissue from an affected individual indicated that this variant results in skipping of exon 16. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_Strong, PM2, PVS1_Moderate, PP3, PP4.

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant replaces glycine with serine at codon 1186 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 in yeast suggest that this variant does not disrupt copper transport activity, however, there could be a trafficking defect (PMID: 18203200). In addition, this variant alters the conserved, last c.G nucleotide of exon 16 and has been shown to cause in-frame skipping of exon 16 of the ATP7B gene (PMID: 20491539). ATP7B exon 16 (a.a. 1138-1186) encodes a part of functionally important nucleotide-binding (N) domain (a.a. 1032 - 1196) and contains multiple disease-causing missense variants, such as p.Ile1148Thr, p.Gly1149Ala, p.Arg1151Cys, p.Glu1173Lys and p.Thr1178Ala (ClinVar - ATP7B). This suggests that in-frame skipping of exon 16 due to this c.3556G>A variant is likely to disrupt ATP7B gene function. This variant has been reported in individuals affected with Wilson disease (PMID: 10453196, 10790207, 15967699, 17587212, 21645214, 22484412, 22940187, 29930488, 34400371), including seven individuals in the compound heterozygous state with a second pathogenic ATP7B variant in trans (PMID: 9452121, 20491539, 23556051, 25130000, 34866098). This variant has been identified in 2/249580 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Feb 26, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 29, 2022

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.3556G>A (p.Gly1186Ser) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site, and two predict the variant creates a cryptic 3' acceptor site. This predicted impact on mRNA splicing was confirmed via cDNA sequencing of total RNA from patient liver samples, which showed that the variant causes skipping of exon 16 (Okada_2010). The variant allele was found at a frequency of 8e-06 in 249580 control chromosomes (gnomAD). c.3556G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Wilson Disease (e.g. Yamaguchi_1998, Okada_2010, Kim_2013, Katano_2014). These data indicate that the variant is very likely to be associated with disease. A seperate publication using a yeast complementation assay found that the variant had normal copper transport activity when expressed in a copper transport deficient yeast strain. However, the authors warned that other aspects of normal gene function (e.g. trafficking) may be altered, allowing for no convincing conclusions about the variants effect on protein function (Hsi_2008). Five ClinVar submitters have assessed the variant since 2014: two classify the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.3556G>A (p.Gly1186Ser) variant in ATP7B gene has been observed in individual(s) with Wilson's disease (Gojová, L et al.,2008). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. Studies have shown that this missense change results in skipping of exon 16, but is expected to preserve the integrity of the readingframe (Okada, Toshihide et al., 2010). This variant is reported with the allele frequency 0.0008% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Gly at position 1186 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1186Ser in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of second reportable variant , the molecular diagnosis is not confirmed

Mar 17, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 30, 2024

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.3556G>A, p.(Gly1186Ser) missense variant has been identified in a homozygous or compound heterozygous state in individuals with Wilson disease (PMID: 9452121; 23556051; 25130000). This variant has also been reported in affected individuals with phase unknown (PMID: 15967699; 20453399; 29930488). This variant is not observed at a significant frequency in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. This variant occurs at the intron/exon boundary of exon 16 and is predicted to result in a splicing defect. This has been confirmed experimentally with the variant demonstrated to result in exon skipping of exon 16 in an individual with Wilson disease (PMID: 20491539). The c.3556G>A variant has been classified as pathogenic by multiple submitters in ClinVar. The variant is identified in a homozygous state in the proband. Based on the available evidence, the c.3556G>A, p.(Gly1186Ser) variant is classified as pathogenic for Wilson disease.

Jun 03, 2025

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Apr 11, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3556G>A pathogenic mutation (also known as p.G1186S), located in coding exon 16 of the ATP7B gene, results from a G to A substitution at nucleotide position 3556. The amino acid change results in glycine to serine at codon 1186, an amino acid with similar properties. This alteration has been identified in the compound heterozygous state in several patients with Wilson disease (Yamaguchi A et al. Hum Mutat 1998;Suppl1:S320-2; Okada T et al. Scand J Gastroenterol 2010; 45 (10) :1232-7; Kim JW et al. World J Hepatol 2013; 5(3):156-9). The c.3556G>A pathogenic mutation changes the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. In addition, this mutation has been shown to cause exon 16 skipping as verified by RT-PCR using total RNA extracted from the liver of a patient with Wilson disease (Okada T et al. Scand J Gastroenterol 2010; 45 (10) :1232-7). In our internal cohort, this alteration was detected in trans with a known pathogenic mutation in ATP7B in an individual with Wilson disease. Based on the supporting evidence, c.3556G>A is interpreted as a disease-causing mutation.

not provided

Pathogenic:1

Oct 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP5, PM2_moderate, PM3, PM5

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

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

PhyloP100

5.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.87

Sift

Benign

0.045

D;T;D;D;D;.;T

Sift4G

Benign

0.069

T;T;T;T;D;T;T

Vest4

0.77

ClinPred

0.97

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.54

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

Splicevardb

3.0

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.78

Position offset: 0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over