rs193922103

chr13-51958361-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr13-51958359-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2679816.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 id is 35706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958361-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2305A>G	p.Met769Val	missense_variant	8/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2305A>G	p.Met769Val	missense_variant	8/21	1	NM_000053.4	P1

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

GnomAD3 exomes AF: 0.0000681 AC: 17 AN: 249552 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135390

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: 0.000150

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000149

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 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

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2017	- -
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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	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). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 9837819, 22240481). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 11, 2019	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. The methionine at codon 769 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. 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. 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. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. Nicastro E et al. Genotype-phenotype correlation in Italian children with Wilson's disease. J Hepatol. 2009 Mar;50(3):555-61. 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. 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. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Apr 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 25, 2022	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2021	Published functional studies found M767V is associated with significantly reduced copper uptake and decreased thermal stability compared to wildtype (Forbes et al., 1998; Huster et al., 2012); 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: 27535533, 31980526, 21610751, 29321352, 10942420, 12557139, 22240481, 11690702, 14986826, 16939419, 17717039, 24253677, 29431110, 19118915, 27022412, 11405812, 10502777, 9311736, 23518715, 22692182, 11093740, 7626145, 20517649, 9837819, 18371106) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ATP7B: PM1, PM2, PM3, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2021	PP3, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 17, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2017

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 v4.3

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;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;B;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922103; hg19: chr13-52532497;