rs72552255

chr13-51946414-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000053.4(ATP7B):c.2930C>T(p.Thr977Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,614,070 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. T977K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 9.94

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 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 13-51946414-G-A is Pathogenic according to our data. Variant chr13-51946414-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946414-G-A is described in Lovd as [Pathogenic]. Variant chr13-51946414-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2930C>T	p.Thr977Met	missense_variant	13/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2930C>T	p.Thr977Met	missense_variant	13/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000842 AC: 21 AN: 249418 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135340

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.000184 AC XY: 134 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74390

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000827 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Thr977Met variant in ATP7B has been previously reported in many individuals with Wilson disease, including at least 3 homozygotes and 8 compound heterozygotes (Aggarwal 2013, Coffey 2013, Folhoffer 2007, Margarit 2005, Moller 2001, Waldenstrom 1996). This variant has been identified in 25/280830 of the total chromosomes in gnomAD, with the highest frequency of 0.016% (5/30592) of South Asian chromosomes. This frequency is low enough to be consistent with a recessive carrier frequency. A functional study indicated that this variant does not rescue CCC2 (homologous to ATP7A and ATP7B) null yeast cells (Forbes 1998). In addition computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PP4, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2023	The ATP7B c.2930C>T; p.Thr977Met variant (rs72552255) is reported in the literature in multiple individuals and families affected with Wilson disease (Chabik 2014, Coffey 2013, Dong 2016, Firneisz 2002, Loudianos 1998, Waldenstrom 1996, Weiss 2010). Many affected individuals with this variant are homozygous or reported to carry a second pathogenic variant (Coffey 2013, Waldenstrom 1996, Weiss 2010). This variant is also reported in ClinVar (Variation ID: 35710). It is found in the general population with an overall allele frequency of 0.009% (25/280830 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein shows that it fails to rescue a knockout yeast cell line (Forbes 1998). Based on available information, this variant is considered to be pathogenic. References: Chabik et al. Concordance rates of Wilson's disease phenotype among siblings. J Inherit Metab Dis. 2014 Jan;37(1):131-5. PMID: 23774950. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Firneisz G et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002 Feb 15;108(1):23-8. PMID: 11857545. Forbes and Cox 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. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. PMID: 9671269. Waldenstrom et al. Efficient detection of mutations in Wilson disease by manifold sequencing. 1996 Nov 1;37(3):303-9. PMID: 8938442. Weiss 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2021	DNA sequence analysis of the ATP7B gene demonstrated a sequence change, c.2930C>T, in exon 13 that results in an amino acid change, p.Thr977Met. The p.Thr977Met change affects a highly conserved amino acid residue located in a transmembrane domain of the ATP7B protein. The p.Thr977Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been reported in multiple individuals with Wilson disease in both homozygous and compound heterozygous states (PMID: 27022412, 32291276, 11857545,20517649). This sequence change has been described in the gnomAD database with a frequency of 0.012% in the non-Finnish European subpopulation (dbSNP rs72552255). Yeast complementation assay showed that this sequence change resulted in a nonfunctional protein and was unable to complement ccc2 mutant yeast (PMID: 9837819). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	Variant summary: ATP7B c.2930C>T (p.Thr977Met) results in a non-conservative amino acid change in 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 8.4e-05 in 249606 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.2930C>T has been reported in the literature in multiple individuals (both compound heterozygous and homozygous state) affected with Wilson Disease (e.g. Loudianos_1998, Vrabelova_2005, Aggarwal_2013). These data indicate that the variant is very likely to be associated with disease. In yeast complementation assays, based on the ability of ATP7B to complement the high-affinity iron-uptake deficiency of the yeast mutant ccc2, the variant resulted in a nonfunctional protein that is completely unable to complement ccc2 mutant yeast (Forbes_1998). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 977 of the ATP7B protein (p.Thr977Met). This variant is present in population databases (rs72552255, gnomAD 0.02%). This missense change has been observed in individuals with Wilson disease (PMID: 8938442, 11857545, 17272994, 18483695, 20517649, 21610751, 21682854, 22774841, 23551039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35710). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with methionine at codon 977 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 that this variant disrupts the ability to rescue function in ccc2 knockout yeast cells (PMID: 9837819). This variant has been reported in many individuals affected with Wilson disease (PMID: 8938442, 9671269, 10502777, 11857545, 15967699, 17272994, 18483695, 20517649, 21610751, 21682854, 22774841, 23518715, 23551039, 23774950, 27022412, 28488633, 28753182, 29163329, 30230192, 31059521), including in several families where this variant co-segregated with disease (PMID: 22774841, 28488633). In a number of individuals, this variant was reported in the compound heterozygous state or the homozygous state (PMID: 8938442, 17272994, 20517649, 21682854, 22774841, 23518715, 28488633, 30230192, 31059521). This variant has been identified in 25/280830 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	Myriad Genetics, Inc.	Jan 06, 2020	NM_000053.3(ATP7B):c.2930C>T(T977M) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 23518715, 9837819 and 8938442. Classification of NM_000053.3(ATP7B):c.2930C>T(T977M) 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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2022	PP3, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	Functional studies found that the T977M variant was unable to complement ccc2 yeast, which demonstrates that this variant results in a nonfunctional protein (Forbes et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23774950, 31589614, 34400371, 35103209, 20517649, 9837819, 22692182, 8938442, 7626145, 27022412, 11857545, 32291276, 32043565, 30275481, 35762218, 35470480) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2015

The p.T977M pathogenic mutation (also known as c.2930C>T), located in coding exon 13 of the ATP7B gene, results from a C to T substitution at nucleotide position 2930. The threonine at codon 977 is replaced by methionine, an amino acid with similar properties. This mutation has been detected in multiple individuals with clinical diagnoses of Wilson disease in both the homozygous and heterozygous forms (Weiss KH, et al. J. Inherit. Metab. Dis. 2010;33 Suppl 3():S233-40; Chabik G, et al. J. Inherit. Metab. Dis. 2014;37(1):131-5; Waldenström E, et al. Genomics 1996;37(3):303-9). In addition, one yeast complementation assay showed that this protein is unable to complement the ccc2 mutant yeast, even when over expressed (Forbes JR, et al. Am. J. Hum. Genet. 1998;63(6):1663-74). A separate study, using homology modeling of the ATP7B core, showed that the 977 position is sensitive to mutations (Schushan M, et al. Metallomics 2012;4(7):669-78). Based on the supporting evidence, p.T977M is interpreted as a disease-causing mutation. -

ATP7B-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The ATP7B c.2930C>T variant is predicted to result in the amino acid substitution p.Thr977Met. This variant has been reported in the homozygous and compound heterozygous states in individuals with Wilson disease (Loudianos et al. 1998. PubMed ID: 9671269; Chabik et al. 2014. PubMed ID: 23774950; Dong et al. 2016. PubMed ID: 27022412). In-vitro functional studies support the pathogenicity of this variant (Forbes et al. 1998. PubMed ID: 9837819). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.95
MVP		1.0
MPC		0.38
ClinPred		0.84	D
GERP RS		5.2
Varity_R		0.90
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: rs72552255; hg19: chr13-52520550;