rs121907998

Positions:

chr13-51961849-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000053.4(ATP7B):c.1934T>G(p.Met645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 2.49

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-51961849-A-C is Pathogenic according to our data. Variant chr13-51961849-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51961849-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.1934T>G	p.Met645Arg	missense_variant	6/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1934T>G	p.Met645Arg	missense_variant	6/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00144

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:

0.00382

GnomAD3 exomes

AF:

0.000517

AC:

129

AN:

249580

Hom.:

AF XY:

0.000487

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000989

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000944

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000414

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000485

AC:

ExAC

AF:

0.000505

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:17

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 645 of the ATP7B protein (p.Met645Arg). This variant is present in population databases (rs121907998, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 9311736, 9482578, 9671269, 11093740, 15952988, 19118915, 21832955). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3862). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 9311736, 22240481). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	Across a selection of available literature, the c.1934T>G (p.Met645Arg) variant has been identified in a compound heterozygous state in at least 23 patients with Wilson disease (Shah et al. 1997; Kalinsky et al. 1998; Deguti et al. 2004; Margarit at al. 2005). The p.Met645Arg variant was absent from 195 controls but is reported at a frequency of 0.00285 in the Latino population of the Exome Aggregation Consortium. The p.Met645Arg variant results in a change of a neutral nonpolar residue to a basic residue. The variant is located in trans-membrane region 1, hence this substitution is expected to disrupt the structure of the transmembrane domain. Functional studies in Sf9 cells demonstrated that the variant displayed copper uptake activity that was indistinguishable from wild type, however the variant was hyperphosphorylated compared to wild type ATP7B (Huster et al. 2012). Studies in SV40-transformed ATP7A-null cells also showed that the p.Met645Arg variant and other missense variants do not disrupt copper transport activity (Braiterman et al. 2014). The biochemical defect for this variant therefore remains to be elucidated. Based on the clinical evidence from the literature, the p.Met645Arg variant is classified as pathogenic for Wilson disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2023	The ATP7B c.1934T>G; p.Met645Arg variant (rs121907998) has been reported in numerous individuals with Wilson disease who were compound heterozygous with another pathogenic variant (Coffey 2013, Deguti 2004, Garcia-Villarreal 2000, Kalinsky 1998, Loudianos 1998, Margarit 2005, Shah 1997). One study of a Spanish Wilson disease cohort observed this variant in 55% of affected individuals (Margarit 2005). This variant is reported in ClinVar (Variation ID: 3862) and is found in the general population with an overall allele frequency of 0.05% (133/280976 alleles) in the Genome Aggregation Database. Functional studies show the variant protein becomes hyperphosphorylated but otherwise has similar copper uptake activity as wild type ATP7B protein (Braiterman 2014, Huster 2012); therefore, the disease-causing mechanism of this variant is unclear. However, based on available information, including its prevalence in affected individuals, the p.Met645Arg variant is considered pathogenic. References: Braiterman LT et al. Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):E1364-73. PMID: 24706876. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. PMID: 15024742. Garcia-Villarreal L et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology. 2000 Dec;32(6):1329-36. PMID: 11093740. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. PMID: 9482578. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. PMID: 9671269. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. PMID: 15952988. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 01, 2021	NM_000053.3(ATP7B):c.1934T>G(M645R) is a missense variant classified as likely pathogenic in the context of Wilson disease. M645R has been observed in cases with relevant disease (PMID: 23518715, 19118915, 32043565, 33159804, 15952988, 23962630). Functional assessments of this variant are available in the literature (PMID: 24706876). M645R has been observed in population frequency databases (gnomAD: AMR 0.22%). In summary, NM_000053.3(ATP7B):c.1934T>G(M645R) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces methionine with arginine at codon 645 of the ATP7B protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has shown to cause almost complete, out-of-frame skipping of exon 6 in mini-gene RNA assays using four different cell lines (PMID: 32284880). In compound heterozygous or homozygous HepG2 cell lines that were edited for this c.1934T>C variant using CRISPR/Cas9 technology, the amount of full length transcript was reduced by more than 70%, consistent with significantly reduced ATP7B protein expression in these cells (PMID: 32284880). This variant has been reported in over 50 individuals affected with Wilson disease (PMID: 9311736, 9482578, 9671279, 15024742, 15952988, 17300695, 17433323, 17949296, 19118915, 21832955, 22484412, 23518715, 23962630, 24706876, 32043565, 33159804). In over 30 of these individuals, this variant was reported in the compound heterozygous or homozygous state (PMID: 9482578, 15024742, 15952988, 19118915, 22484412, 23518715, 23962630, 33159804). This variant is highly prevalent among Wilson disease patients of Spanish descent and has been observed in 55% of Spanish individuals with Wilson disease (PMID: 15952988). This variant has been identified in 133/280976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The ATP7B c.1934T>G (p.M645R) variant has previously been reported in the homozygous and compound heterozygous state in individuals with Wilson disease (PMID: 11093740; 9482578; 9671269; 15952988; 19118915; 20301685). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	This missense variant replaces methionine with arginine at codon 645 of the ATP7B protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has shown to cause almost complete, out-of-frame skipping of exon 6 in mini-gene RNA assays using four different cell lines (PMID: 32284880). In compound heterozygous or homozygous HepG2 cell lines that were edited for this c.1934T>C variant using CRISPR/Cas9 technology, the amount of full length transcript was reduced by more than 70%, consistent with significantly reduced ATP7B protein expression in these cells (PMID: 32284880). This variant has been reported in over 50 individuals affected with Wilson disease (PMID: 9311736, 9482578, 9671279, 15024742, 15952988, 17300695, 17433323, 17949296, 19118915, 21832955, 22484412, 23518715, 23962630, 24706876, 32043565, 33159804). In over 30 of these individuals, this variant was reported in the compound heterozygous or homozygous state (PMID: 9482578, 15024742, 15952988, 19118915, 22484412, 23518715, 23962630, 33159804). This variant is highly prevalent among Wilson disease patients of Spanish descent and has been observed in 55% of Spanish individuals with Wilson disease (PMID: 15952988). This variant has been identified in 133/280976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 27, 2020	This variant is interpreted as likely pathogenic for Wilson disease, autosomal recessive. NM_000053.4:c.1934T>G has been identified in a compound heterozygous state in multiple patients with Wilson disease (for example PMID:9482578, 9671269, 11093740, 15952988, 17949296), and is present in gnomAD at a frequency compatible with disease prevalence. Functional studies have been published, but results are contradictory. Some studies (PubMed:17919502, 24706876, 22240481) show that the variant has no functional effect. Merico et al. (PubMed:32284880) demonstrate that NM_000053.4:c.1934T>G causes 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, and reduced protein expression. The following ACMG Tag(s) were applied to variant interpretation: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3-Very Strong => For recessive disorders, detected in trans with a pathogenic variant. Criterion has been upgraded because the variant has been detected in multiple patients. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 09, 2023	PM3_VSTR, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	Published functional studies demonstrate nearly complete exon-skipping when the variant was transfected into different cell lines (Merico et al., 2019); This variant is associated with the following publications: (PMID: 32043565, 31980526, 32067425, 32284880, 32154060, 15952988, 27285482, 27437191, 17919502, 27398169, 25525159, 27415407, 28856630, 9311736, 24706876, 28433111, 22692182, 23962630, 22240481, 24253677, 29482223) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2021

The c.1934T>G (p.M645R) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a T to G substitution at nucleotide position 1934, causing the methionine (M) at amino acid position 645 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the ATP7B c.1934T>G alteration was observed in 0.05% (133/280976) of total alleles studied, with a frequency of 0.23% (24/10362) in the Ashkenazi Jewish subpopulation. This mutation has been detected in many compound heterozygous individuals with Wilson Disease, some of whom had only mild symptoms (Margarit, 2005; Kalinsky, 1998; Loudianos, 1998; Shah, 1997; García-Villarreal, 2000; Peña-Quintana, 2012; Arruda, 2014). Minigene analysis of this variant in four cell lines demonstrated that this variant results in increased exon skipping compared to wildtype, with Hep2G cells compound heterozygous for this mutation expressing 15% of wild type levels and homozygous cells expressing approximately 30% (Merico, 2020). The in silico prediction for the p.M645R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

ATP7B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The ATP7B c.1934T>G variant is predicted to result in the amino acid substitution p.Met645Arg. This variant has been reported in the homozygous or compound heterozygous state in several patients with Wilson disease (see for example Shah et al. 1997. PubMed ID: 9311736; Kalinsky et al.1998. PubMed ID: 9482578; Loudianos et al. 1998. PubMed ID: 9671269). Experimental studies of the effect of this variant on ATP7B transport activity are conflicting. One study observed a decrease in copper transport in lymphoblast cell lines from patients homozygous for c.1934T>G (Shah et al. 1997. PubMed ID: 9311736). In contrast, this variant apparently had no affect on transporter activity when heterologously expressed in a model insect cell line (Huster et al. 2012. PubMed ID: 22240481). Based on the collective information, particularly that from patients, we interpret the c.1934T>G variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.28

T;T;.;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.22

T;T;T;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.061

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-1.2

N;.;.;.;.

MutationTaster

Benign

0.018

A;A;A;A;A;A;A;A

PrimateAI

Benign

0.26

PROVEAN

Benign

0.43

N;N;N;.;N

REVEL

Uncertain

0.48

Sift

Benign

0.58

T;T;T;.;T

Sift4G

Benign

0.44

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.33

MVP

0.88

MPC

0.086

ClinPred

0.028

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -12

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