rs768671894

chr13-51950328-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):c.2519C>T(p.Pro840Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. P840T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.89

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 13-51950328-G-A is Pathogenic according to our data. Variant chr13-51950328-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 188879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2519C>T	p.Pro840Leu	missense_variant	10/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2519C>T	p.Pro840Leu	missense_variant	10/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461870 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2016	Variant summary: The variant of interest affects a conserved nucleotide and results in replacing a small and kink-inducing Proline residue with a bulky and hydrophobic Leucine. 5/5 in silico prediction tools predict deleterious outcome by this substitution. The variant was found in the broad and large cohort of ExAC at an allele frequency of 1/120734 (0.0008%), which does not exceed the maximal expected allele frequency of a disease causing ATP7B allele (0.54%), further supporting a pathogenic nature for the variant. In addition, there are several Wilsons Disease patients reported to have the variant in compound heterozygote module (Amson_2012, Gu_2013, Nicastro_2010). Independent functional studies have shown that the variant results in the impairment of cellular copper transfer (Huster_2012 , Schushan_2012), which is consistent with a disease causing outcome. Considering all evidence, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 22, 2019	The ATP7B c.2519C>T; p.Pro840Leu variant (rs768671894) is reported in the literature in individuals affected with Wilson disease, including multiple individuals that carried a second pathogenic variant (Amson 2012, Gu 2013, Loudianos 1998, Nicastro 2010). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 840 is highly conserved, and functional studies indicate that this variant has substantially decreased copper transport activity (Huster 2012). Based on available information, this variant is considered to be pathogenic. References: Amson M et al. Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum. Can J Gastroenterol. 2012 Jun;26(6):330-2. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Nicastro E et al. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology. 2010 Dec;52(6):1948-56. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 840 of the ATP7B protein (p.Pro840Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17272994, 22720273, 23843956). 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: 188879). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces proline with leucine at codon 840 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). A functional study has shown that the variant results in a significant decrease in copper transport activity and increased catalytic phosphorylation activity (PMID: 22240481). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 9671269, 10544227, 17272994, 20958917, 20967755, 22308153, 22720273, 23843956, 24661374, 30232804, 34257423), including in the homozygous state with no evidence of consanguinity (PMID: 30232804) and in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 10544227, 17272994, 20967755, 22720273, 23843956, 24661374, 30232804). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2016

The P840L pathogenic variant in the ATP7B gene has been reported previously in several individuals with Wilson disease (Loudiano et al., 1998; Huster et al., 2012; Gu et al., 2013). This variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P840L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In-silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies demonstrate that the P840L variant results in impaired copper uptake (Huster et al., 2012). Missense variants in nearby residues (G836E, D842N, D842Y, G843R) have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P840L as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.1	D;D;D;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;P;D;D
Vest4		0.99
MutPred		0.98		Loss of disorder (P = 0.0439);.;.;.;.;Loss of disorder (P = 0.0439);
MVP		0.98
MPC		0.38
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs768671894; hg19: chr13-52524464; COSMIC: COSV54435514; COSMIC: COSV54435514;