13-51958361-T-C

Variant names:

• chr13-51958361-T-C
• rs193922103
• NM_000053.4:c.2305A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2305A>G​(p.Met769Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,614,022 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M769I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.96
• Publications: 30 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51958359-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2679816.
• 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, 0.862
• PP5: Variant 13-51958361-T-C is Pathogenic according to our data. Variant chr13-51958361-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 35706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.2305A>G	p.Met769Val	missense	Exon 8 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.2305A>G	p.Met769Val	missense	Exon 9 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.2305A>G	p.Met769Val	missense	Exon 9 of 22	NP_001393441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2305A>G	p.Met769Val	missense	Exon 8 of 21	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.2161A>G	p.Met721Val	missense	Exon 8 of 21	ENSP00000489398.1
	ATP7B	ENST00000418097.7	TSL:1	c.2305A>G	p.Met769Val	missense	Exon 8 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000681 AC: 17 AN: 249552 AF XY: 0.0000517

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000264 AC: 386 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000264 AC XY: 192 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1112012

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000661 AC: 8

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:12

May 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.2305A>G; p.Met769Val variant (rs193922103) is reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with Wilson disease (Caca 2001, Curtis 1999, Garcia-Villarreal 2000, Moller 2011, Nicastro 2009, Weiss 2010, Wu 2001). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 35706), and is found in the non-Finnish European population with an allele frequency of 0.016% (20/128,686 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.906). Functional analyses of the variant protein show reduced copper transport activity (Forbes and Cox 1998, Huster 2012). Based on available information, this variant is considered to be pathogenic. References: Caca K et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol. 2001 Nov;35(5):575-81. PMID:11690702. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. PMID: 10502777. Forbes JR and Cox DW et al. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet. 1998 Dec;63(6):1663-74. PMID: 9837819. 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. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. PMID: 21610751. Nicastro E et al. Genotype-phenotype correlation in Italian children with Wilson's disease. J Hepatol. 2009 Mar;50(3):555-61. PMID: 19118915. Weiss KH et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40. PMID: 20517649. Wu ZY et al. Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Arch Neurol. 2001 Jun;58(6):971-6. PMID: 11405812.

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Met769Val variant in ATP7B has been identified in the homozygous or compound heterozygous state in at least 6 individuals with Wilson disease (Curtis 1999, Caca 2001, Lepori 2007, Nicastro 2009, Weiss 2010, Moller 2011). It has also been identified in 0.016% (20/128686) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 35706). In vitro functional studies support an impact on protein function (Forbes 2000, Huster 2012, ). In addition, computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP4, PS3_Supporting.

Aug 14, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

Feb 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 23, 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 methionine with valine at codon 769 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 this variant's impact on copper transport activity (PMID: 9837819, 10942420, 12557139, 18203200, 17717039, 22240481, 22806248). This variant has been reported in individuals affected with Wilson disease (PMID: 10502777, 11405812, 11690702, 15202786, 17449133, 17949296, 19118915, 20082719, 20517649, 21610751, 23518715, 23982005, 27022412, 27706781, 29321352, 29431110, 31980526, 33159804, 33640437, 34400371). In a number of these individuals, this variant was confirmed to be in the compound heterozygous state (PMID: 29321352, 33159804, 33640437) or the homozygous state (PMID: 19118915, 22806248, 32028086). This variant has been identified in 20/280946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 769 of the ATP7B protein (p.Met769Val). This variant is present in population databases (rs193922103, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 7626145, 11690702, 19118915, 20517649, 21610751). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35706). 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 have shown that this missense change affects ATP7B function (PMID: 9837819, 22240481). For these reasons, this variant has been classified as Pathogenic.

Dec 24, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000053.3(ATP7B):c.2305A>G(M769V) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9837819, 19118915, 23518715, 22692182, 24253677, 22240481 and 10942420. Classification of NM_000053.3(ATP7B):c.2305A>G(M769V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:5

Feb 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a second ATP7B pathogenic variant in unrelated patients with Wilson disease referred for genetic testing at GeneDx and in published literature; however, it is not known whether the variants occurred on the same allele (in cis) or on different alleles (in trans) in all cases (PMID: 33159804, 20517649, 21610751); Published functional studies found M769V is associated with significantly reduced copper uptake and decreased thermal stability compared to wildtype (PMID: 22240481, 9837819); 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: 9311736, 11405812, 19118915, 24253677, 18371106, 21610751, 34400371, 35271763, 9837819, 20517649, 7626145, 11093740, 22692182, 23518715, 10502777, 27022412, 29431110, 17717039, 16939419, 14986826, 11690702, 12557139, 10942420, 29321352, 31980526, 33159804, 27535533, 22240481)

Jun 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 17, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM3:Strong, PM1, PM2, PM5, PP3, PS3:Supporting

May 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2_moderate, PM5

Inborn genetic diseases Pathogenic:1

Jun 22, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M769V pathogenic mutation (also known as c.2305A>G), located in coding exon 8 of the ATP7B gene, results from an A to G substitution at nucleotide position 2305. The methionine at codon 769 is replaced by valine, an amino acid with highly similar properties. This mutation was reported in multiple unrelated individuals (Curtis D et al. Hum. Mutat., 1999;14:304-11; García-Villarreal L et al. Hepatology, 2000 Dec;32:1329-36; Caca K et al. J. Hepatol., 2001 Nov;35:575-81; Weiss KH et al. J. Inherit. Metab. Dis., 2010 Dec;33 Suppl 3:S233-40), including two homozygous individuals with hepatic Wilson disease (Nicastro E et al. J. Hepatol., 2009 Mar;50:555-61). Functional studies demonstrated that this mutation impairs the protein function (Forbes JR et al. Am. J. Hum. Genet., 1998 Dec;63:1663-74; Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.3	L
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.88
MPC		0.38
ClinPred		0.40	T
GERP RS		5.4
Varity_R		0.84
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922103; hg19: chr13-52532497;