rs374094065

chr13-51944161-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000053.4(ATP7B):c.3191A>C(p.Glu1064Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. E1064K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 7.97

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 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr13-51944162-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821
• PP5: Variant 13-51944161-T-G is Pathogenic according to our data. Variant chr13-51944161-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51944161-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3191A>C	p.Glu1064Ala	missense_variant	14/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3191A>C	p.Glu1064Ala	missense_variant	14/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000148 AC: 37 AN: 249378 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461872 Hom.: 1 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 03, 2024	This missense variant replaces glutamic acid with alanine at codon 1064 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). This variant alters a conserved glutamic acid residue in the N (ATP nucleotide-binding) domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study has shown that this variant causes a complete loss of the ATP binding function of ATP7B protein (PMID: 15205462). This variant has been observed in multiple individuals affected with Wilson disease in the homozygous state (PMID: 9482578) and in the compound heterozygous state with another pathogenic variant in the same gene (PMID: 15723329, 16175588, 23518715, 23518715, 36096368, 33640437, 36096368). This variant has been identified in 37/249378 chromosomes (33/10068 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Glu1064Lys, is known to cause disease (ClinVar Variation ID: 550969), indicating that glutamic acid at this position is important for ATP7B protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2021	The ATP7B c.3191A>C; p.Glu1064Ala variant (rs374094065) has been described in the compound heterozygous state in several patients with Wilson disease, often in-trans with the common pathogenic p.His1069Gln variant (Ala 2005, Coffey 2013, Perri 2005). It is reported in ClinVar (Variation ID: 370081) and observed in the general population at an overall frequency of 0.015% (37/249378 alleles) with increased frequency in the Ashkenazi Jewish population (0.33%) in the Genome Aggregation Database. The glutamic acid at codon 1064 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.976). Consistent with this, functional analysis of the variant protein demonstrates a complete loss of ATP binding (Morgan 2004). Additionally, another variant at this position (c.3190G>A; p.Glu1064Lys) has been described in individuals with Wilsons disease and is considered pathogenic (Balashova 2020). Based on available information, the p.Glu1064Ala variant is considered pathogenic. References: Ala A et al. Wilson disease in septuagenarian siblings: Raising the bar for diagnosis. Hepatology. 2005 Mar;41(3):668-70. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Morgan C et al. The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem. 2004 Aug 27;279(35):36363-71. Perri R et al. Wilson Disease--keeping the bar for diagnosis raised. Hepatology. 2005 Oct;42(4):974. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1064 of the ATP7B protein (p.Glu1064Ala). This variant is present in population databases (rs374094065, gnomAD 0.3%). This missense change has been observed in individual(s) with Wilson disease (PMID: 2610069, 9311736, 15723329, 16175588, 23518715). 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: 370081). 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: 15205462). This variant disrupts the p.Glu1064 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15723329, 17272994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2018	The p.Glu1064Ala variant in ATP7B has been reported in the compound heterozygous state with the p.His1069Gln variant in 3 individuals with Wilson disease, inclu ding at least 2 with mild disease, and segregated with disease in one affected r elative (Ala 2005, Perri 2005, Coffey 2013). This variant has been identified in 0.33% (32/9846) of Ashkenazi Jewish chromosomes and 4/111606 European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ) and is reported in ClinVar (Variation ID:370081). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evi dence that the p.Glu1064Ala variant may impact protein function (Morgan 2004, Di mitriev 2011, Schushan 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation a nalysis suggest that the p.Glu1064Ala variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. Additionally, another variant at the same residue, p.Glu1061Lys, has been identified in patie nts with Wilson disease, suggesting variation at this site may not be tolerated. In summary, although additional studies are required to fully establish its cli nical significance, the p.Glu1064Ala variant is likely pathogenic. ACMG/AMP crit eria applied: PM3_Strong, PM5, PS3_Moderate, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	This missense variant replaces glutamic acid with alanine at codon 1064 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). This variant alters a conserved glutamic acid residue in the N (ATP nucleotide-binding) domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study has shown that this variant causes a complete loss of the ATP binding function of ATP7B protein (PMID: 15205462). This variant has been observed in multiple individuals affected with Wilson disease in the homozygous state (PMID: 9482578) and in the compound heterozygous state with another pathogenic variant in the same gene (PMID: 15723329, 16175588, 23518715, 23518715, 36096368, 33640437, 36096368). This variant has been identified in 37/249378 chromosomes (33/10068 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Glu1064Lys, is known to cause disease (ClinVar Variation ID: 550969), indicating that glutamic acid at this position is important for ATP7B protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 20, 2017	The ATP7B c.3191A>C (p.Glu1064Ala) missense variant has been reported in three studies in which it was found in a total of four individuals affected with Wilson disease, including in three in a compound heterozygous state (two of whom were siblings and carried the most common pathogenic variant associated with Wilson disease, p.His1069Gln, in trans) and in one with unknown zygosity (Shah et al. 1997; Kalinsky et al. 1998; Ala et al. 2005). The p.Glu1064Ala variant was present in a heterozygous state in 1/200 control chromosomes and is reported at a frequency of 0.00325 in the Ashkenazi Jewish population of the Genome Aggregation Database (Kalinsky et al. 1998). The variant occurs at a residue that is highly conserved across P1-ATPases in the helical hairpin region of the N-terminal domain, close to the most common pathogenic variant associated with Wilson disease. The p.Glu1064Ala variant has been shown to result in loss of ATP and ADP binding (Morgan et al. 2004; Dmitriev et al. 2011). In vivo structural NMR studies showed that the variant did not affect the overall fold of the N-domain containing the variant but did produce a more open structure which caused misalignment of ATP-binding residues which may account for the loss of ATP binding ability. In contrast, the p.Glu1064Ala variant did not affect stability or targeting of the protein in HEK293TRex cells (Dmitriev et al. 2011). However, based on the evidence, the p.Glu1064Ala variant is classified as a likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2023	Variant summary: ATP7B c.3191A>C (p.Glu1064Ala) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251578 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.3191A>C has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Kalinsky_1998, Ala_2005, Perri_2005, Kuppala_2009, Coffey_2013, and Collins_2021). In at least four of these affected individuals, this variant has been found in trans with another previously established deleterious variant in the same gene (p.His1069Glu). These data indicate that the variant is likely to be associated with disease. Functional studies suggest that this missense change disrupts the protein's ability to bind ATP completely which is consistent with the loss of function of the mutant protein (e.g. Morgan_2004, Dmitriev_2011). Thirteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=8) or likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 07, 2022	PP1, PP3, PP4, PM2, PM3_supporting, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	Functional studies found that this variant results in loss of ATP binding (Morgan et al., 2004; Dmitriev et al., 2011); 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: 31751128, 22692182, 23518715, 17272994, 26483271, 16175588, 31624327, 15723329, 15205462, 21398519, 9311736, 17717039, 9482578, 2610069, 32028086, 27415407) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2016

The p.E1064A pathogenic mutation (also known as c.3191A>C), located in coding exon 14 of the ATP7B gene, results from an A to C substitution at nucleotide position 3191. The glutamic acid at codon 1064 is replaced by alanine, an amino acid with dissimilar properties. This mutation was detected in two siblings with Wilson disease and the p.H1069Q pathogenic mutation in trans (Ala A, Hepatology 2005 Mar; 41(3):668-70). In addition, functional studies show this alteration results in the complete loss of ATP binding (Morgan CT, J. Biol. Chem. 2004 Aug; 279(35):36363-71). Based on the supporting evidence, p.E1064A is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;.;T
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;P;D;D;D
Vest4		0.90
MVP		1.0
MPC		0.39
ClinPred		0.72	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.94
gMVP		0.88

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: rs374094065; hg19: chr13-52518297;