rs72552255
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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 (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
15
3
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a transmembrane_region Helical (size 21) in uniprot entity ATP7B_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.2930C>T | p.Thr977Met | missense_variant | 13/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP7B | ENST00000242839.10 | c.2930C>T | p.Thr977Met | missense_variant | 13/21 | 1 | NM_000053.4 | ENSP00000242839.5 |
Frequencies
GnomAD3 genomes 0.000112 AC: 17AN: 152262Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000842 AC: 21AN: 249418Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135340
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GnomAD4 exome AF: 0.000182 AC: 266AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.000184 AC XY: 134AN XY: 727202
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GnomAD4 genome 0.000112 AC: 17AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74390
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 10, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| 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, 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 | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | The missense c.2930C>T p.Thr977Met variant in ATP7B gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Wilson disease Li J, et al., 2020; Singh N, et al., 2019; Aggarwal A, et al., 2013; Abdelghaffar TY, et al., 2008. It has also been observed to segregate with disease in related individuals. Functional studies showed that this variant was unable to complement ccc2 yeast, further resulting in a nonfunctional protein Forbes JR & Cox DW. 1998. The p.Thr977Met variant is present with allele frequency of 0.008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 977 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 30, 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. This variant alters a residue in a transmembrane domain of the ATP7B protein (a.a. 970 - 1003), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). 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 confirmed to be 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 | 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 | 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 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 02, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
not provided Pathogenic:3
| 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) - |
| 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 | Nov 02, 2023 | PP3, PP4, PM2_moderate, PM3, PS3, PS4_moderate - |
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 disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at