13-51946372-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP5BS2
The NM_000053.4(ATP7B):c.2972C>T(p.Thr991Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,596 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T991A) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0015 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0034 ( 10 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
14
4
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 Uncertain_significance. Variant got 1 ACMG points.
PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000053.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-51946373-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1172921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 13-51946372-G-A is Pathogenic according to our data. Variant chr13-51946372-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35712.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=14, Likely_pathogenic=2, Pathogenic=1}. Variant chr13-51946372-G-A is described in Lovd as [Pathogenic].
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.2972C>T | p.Thr991Met | missense_variant | 13/21 | ENST00000242839.10 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATP7B | ENST00000242839.10 | c.2972C>T | p.Thr991Met | missense_variant | 13/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes 0.00148 AC: 226AN: 152238Hom.: 2 Cov.: 33
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GnomAD3 exomes AF: 0.00120 AC: 298AN: 248580Hom.: 0 AF XY: 0.00120 AC XY: 162AN XY: 134988
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GnomAD4 exome AF: 0.00340 AC: 4963AN: 1461240Hom.: 10 Cov.: 32 AF XY: 0.00325 AC XY: 2363AN XY: 726878
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GnomAD4 genome 0.00148 AC: 226AN: 152356Hom.: 2 Cov.: 33 AF XY: 0.00138 AC XY: 103AN XY: 74514
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:2Uncertain:8
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wilson disease (MIM#277900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (222 heterozygotes, 2 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated E1-E2_ATPase domain (Decipher). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive (ClinVar, PMIDs: 16088907, 17949296, 23518715). This variant has been reported as likely pathogenic/pathogenic twice and 7 times as a variant of unknown significance (ClinVar). In addition, this variant has been reported in Wilson disease patients, although the presence of a second disease-causing variant could not be conclusively determined. Homozygosity of this variant was also identified in a fetus with arthrogryposis, which is inconsistent with Wilson Disease. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. When transfected into yeast cells, this variant was shown to be a mild variant likely to contribute to Wilson disease (PMID: 20333758). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 15, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 12, 2021 | The ATP7B c.2972C>T variant is classified as VUS (PS3_Supporting, PM2, PP3) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 991 of the ATP7B protein (p.Thr991Met). This variant is present in population databases (rs41292782, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Wilson disease (PMID: 16088907, 23518715, 26275891; Invitae). 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: 35712). 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: 20333758). This variant disrupts the p.Thr991 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 05, 2022 | The ATP7B c.2972C>T; p.Thr991Met variant (rs41292782) has been described in two patients with Wilson disease (Cox 2005), and has been implicated as having a mild effect on protein function in a model system (Luoma 2010). This variant has also been described homozygously in a prenatal sample with arthrogryposis (Drury 2015). This variant is reported in ClinVar (Variation ID: 35712) and is found in the non-Finnish European population with an allele frequency of 0.24% (312/128176 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 991 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.927). However, due to limited information, the clinical significance of the p.Thr991Met variant is uncertain at this time. References: Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005 26(3):280. PMID: 16088907. Drury S et al. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn. 2015 Oct;35(10):1010-7. PMID: 26275891. Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 31(5):569-77. PMID: 20333758. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.2972C>T (p.Thr991Met) in ATP7B gene in heterozygous state have be associated with Wilson disease (Lepori_2007, Cox_2005). The variant has been described in few patients with Wilson disease (Cox 2005), and has been implicated as having a mild effect on protein function in a model system (Luoma 2010). This variant is reported with the allele frequency 0.1% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic/variant of unsignificance. The amino acid Thr at position 991 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr991Met in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. In the absence of second reportable variants, the molecular diagnosis cannot be confirmed. - |
| Uncertain significance, 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 991 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 does not affect protein expression but partially disrupts complementation in a yeast assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 16088907, 17949296, 23518715, 27528516, 33258288, 31738409) and in one individual affected with schizophrenia (PMID: 30556376). This variant has been identified in 352/279976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 09, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 16, 2022 | This missense variant replaces threonine with methionine at codon 991 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 does not affect protein expression but partially disrupts complementation in a yeast assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 16088907, 17949296, 23518715, 27528516, 33258288, 31738409) and in one individual affected with schizophrenia (PMID: 30556376). This variant has been identified in 352/279976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Pathogenic:1Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 29, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2022 | 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, 30556376, 31738409, 22692182, 26275891, 27528516, 17949296, 31708252, 31059521, 26206375, 24253677, 34426522, 23235335, 32248359, 30275481, 31815884, 31980526, 33258288, 34620762, 16088907, 20333758, 35287663) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | ATP7B: PM1, PM5, PP3, PS3:Supporting, BS2 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 29, 2022 | PP3, PM2_supporting, PS3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 12, 2016 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2023 | Variant summary: ATP7B c.2972C>T (p.Thr991Met) results in a non-conservative amino acid change located in the Transmembrane 6 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with several publications reporting computational predictions of pathogenicity (Schushan_2012, Khurana_2015, Squitti_2014). The variant allele was found at a frequency of 0.0012 in 250871 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0012 vs 0.0054), allowing no conclusion about variant significance. c.2972C>T was initially reported in the literature and subsequently cited by others in heterozygous state in individuals affected with Wilson Disease, without information on the presence of a second ATP7B variant (Lepori_2007, Cox_2005). These data indicate that the variant may be associated with disease. The variant has been reported as a homozygote in a fetus with prenatal diagnosis of arthrogryposis and a diagnosis not compatible with Wilson Disease (Drury_2015). In addition, it has also been observed as a heterozygote or unspecified zygosity in two other individuals. One affected with ataxia and normal levels of copper/cerulloplasmin (heterozygote with a non-specific genotype) and the other with schizophrenia (unspecified zygosity), (Sriretnakumar_2019, Marelli_2016). Most recently, a report cites this variant as among ATP7B variants with a questionable causality and/or penetrance (Wallace_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a mild/intermediate deficit when assessing the ability to complement ccc2, the yeast copper-transporting orthologue of ATP7B, function under low iron conditions at 30 degree C and 37 degree C (Luoma_2010). The physiological relevance of this finding is unclear. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=8, pathogenic/likely pathogenic, n=3). Based on the evidence outlined above, the variant retained its classification as a VUS-possibly pathogenic. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2020 | The c.2972C>T (p.T991M) alteration is located in exon 13 (coding exon 13) of the ATP7B gene. This alteration results from a C to T substitution at nucleotide position 2972, causing the threonine (T) at amino acid position 991 to be replaced by a methionine (M). The p.T991M alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
ATP7B-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The ATP7B c.2972C>T variant is predicted to result in the amino acid substitution p.Thr991Met. This variant has been reported in at least one individual with Wilson disease; however, it is unclear from the literature if a second variant was identified (Cox et al. 2005. PubMed ID: 16088907). Functional studies of the variant protein demonstrated a mild to intermediate deficiency in copper transport (Luoma et al. 2010. PubMed ID: 20333758). However, this variant is documented in the gnomAD general population database with a sub-population frequency of up to 0.24% and with one homozygous individual (https://gnomad.broadinstitute.org/). One study suggested that this variant could have low penetrance or may be non-causative (Wallace and Dooley. 2020. PubMed ID: 32248359); however, no clear evidence was provided. It is listed in the ClinVar database with conflicting interpretations including uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/35712/). Based on the available evidence, we classify the ATP7B c.2972C>T variant to be uncertain. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
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
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;P;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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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