rs587783299

chr13-51961906-C-G

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.1877G>C(p.Gly626Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,613,478 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G626G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.11

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 domain HMA 6 (size 66) in uniprot entity ATP7B_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 13-51961906-C-G is Pathogenic according to our data. Variant chr13-51961906-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 157930.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.1877G>C	p.Gly626Ala	missense_variant	6/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.1877G>C	p.Gly626Ala	missense_variant	6/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

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: 0.00

GnomAD3 exomes AF: 0.0000882 AC: 22 AN: 249516 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000636 AC: 93 AN: 1461374 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2022	Variant summary: ATP7B c.1877G>C (p.Gly626Ala) results in a non-conservative amino acid change located in the heavy metal-associated domain, copper ion-binding (IPR006122) 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 8.8e-05 in 249616 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.1877G>C has been reported in the literature on certain occasions in compound heterozygosity with other pathogenic variants (e.g. p.Gly1061Glu, p.His1069Gln), in multiple individuals affected with Wilson Disease (Bost_2012, Braiterman_2014, Coffey_2013, Figus_1995, Ljubic_2016, Loudianos_1999, Todorov_2005, Collins_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions about the variant effect. Specifically, one study demonstrated the variant to cause partial copper transport activity but normal phosphorylation activity (Huster_2012) while, other studies revealed normal copper transport and trafficking (Braiterman_2014, Hsi_2008). A separate study showed the variant protein retained its ability to interact with COMMD1 but at decreased efficiency (de Bie_2007); however, it is not conclusively established if and how this change could lead to disease. Therefore, these studies do not allow convincing conclusions about the variant effect. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic, n=6; pathogenic, n=1, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 626 of the ATP7B protein (p.Gly626Ala). This variant is present in population databases (rs587783299, gnomAD 0.1%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 24706876, 26799313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly627Ala. ClinVar contains an entry for this variant (Variation ID: 157930). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATP7B function (PMID: 17919502, 18203200, 22240481, 24706876). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces glycine with alanine at codon 626 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 the impact of this variant on protein function (PMID: 18203200, 22240481, 24706876). One study showed this variant partially disrupted copper transport but maintained normal phosphorylation activity (PMID: 22240481), while two other studies showed normal copper transport and localization (PMID: 18203200, 24706876). This variant has been reported in many individuals affected with Wilson disease (PMID: 8533760, 8938442, 9311736, 10544227, 16207219, 18371106, 22677543, 22735241, 23518715, 24706876, 26799313, 33640437, 34400371, 36096368). In a number of these individuals, this variant has been determined to be in the compound heterozygous state with another pathogenic variant (PMID: 23518715, 24706876, 26799313, 33640437). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 24/280910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 27, 2022	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 17, 2021	The sequence change, c.1877G>C, is located in exon 6 and results in an amino acid change, p.Gly626Ala. The p.Gly626Ala change affects a highly conserved amino acid residue located in a transmembrane domain of the ATP7B protein. The p.Gly626Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has previously been described in individuals with Wilson disease together with a pathogenic variant (PMIDs: 8533760, 22735241, 8938442, 24706876). Multiple functional studies have shown conflicting results (PMID: 18203200, 22240481, 24706876). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the non-Finnish European subpopulation (dbSNP rs587783299). These collective evidences indicate that this sequence change is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 28, 2023	PP3, PP4, PM2, PS4_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2021	Multiple functional studies have shown conflicting results (Huster D et al., 2012; de Bie P et al., 2007; Hsi G et al., 2008; Braiterman LT et al., 2014; Shah AB et al., 1997; Shanmugavel KP et al., 2019); 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: 23518715, 16207219, 31598802, 31980526, 22735241, 18371106, 9671269, 24798599, 15994426, 10544227, 29063292, 18286826, 22677543, 8938442, 9311736, 8533760, 24706876, 18203200, 17919502, 22240481) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.1877G>C (p.G626A) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a G to C substitution at nucleotide position 1877, causing the glycine (G) at amino acid position 626 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.009% (24/280910) total alleles studied. The highest observed frequency was 0.097% (10/10362) of Ashkenazi Jewish alleles. This alteration was detected in conjunction with another alteration in ATP7B in multiple individuals with Wilson disease (Collins, 2021; Ljubic, 2016; Coffey, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show no significant alterations to copper transport activity in vitro (Hsi, 2008; Huster, 2012; Braiterman, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.2	D;D;D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;T;D;.;D
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		1.0	D;D;B;P;D
Vest4		0.94
MVP		1.0
MPC		0.39
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587783299; hg19: chr13-52536042;