The ATP7B NM_000053.4:c.3207C>A (NP_000044.2:p.(His1069Gln)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Four independent assays showed impaired ATP binding, with H1069Q failing to saturate even at 600 µM ATP and showing concordant cellular dysfunction. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.ATP7B encodes a copper-transporting ATPase that helps remove excess copper from cells, particularly by exporting copper from the liver into bile. Impaired ATP7B function causes Wilson disease, in which copper accumulates in the liver, brain, and other tissues. ATP7B has no established general role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: four independent assays showed impaired ATP binding, with H1069Q failing to saturate even at 600 µM ATP and showing concordant cellular dysfunction.
Met: H1069Q occurred in 27/42 affected patients versus 0.1058% in NFE gnomAD, yielding OR 1,698.8 (95% CI 901.5-3,201.2), above the >5.0 threshold.
Met, supporting: missense REVEL score 0.909 exceeds the PP3 supporting threshold of 0.644.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 (strong) and PS4 (strong) satisfy the generic ACMG/AMP rule for two strong pathogenic criteria, with PP3 (supporting) additional evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1,523 / 1,614,166 alleles. Recorded AF 0.000943521. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 0.00101864; MAF= 0.10186%, 286/280766 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00531093; MAF= 0.53109%, 55/10356 alleles, homozygotes = 0); grpmax FAF= 0.00258435.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.909. Refer to the recorded PP3/BP4 rationale for interpretation.
41 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 9 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 is met from exact-variant enrichment in 27/42 affected patients versus the ancestry-proximate gnomAD v4.1 NFE frequency, with calculated OR 1,698.8 and approximate 95% CI 901.5-3,201.2.
PP4 is not assessed because patient-level phenotype and family-history information is absent.
PP5 and BP6 are not triggered because ClinVar has no exact-variant expert-panel classification; BP5 is not assessed because no alternate molecular basis is documented for this exact variant.
Allelic evidence is insufficient to confirm PM3 because documented phase testing and pathogenicity of the partner alleles are unavailable.
BP2 is not met because no cis observation with a pathogenic variant is documented and ATP7B Wilson disease is recessive.
The variant is missense, so PP3 and BP4 are adjudicated through the REVEL path only; the same prediction is not double-counted across criteria.
REVEL 0.909 supports PP3 at supporting strength and does not meet BP4.
No criteria match.
PS3 is met at strong strength. Four independent studies directly evaluated ATP7B p.His1069Gln (NM_000053.4:c.3207C>A) using complementary biochemical and cellular assays with wild-type comparators. Morgan et al. demonstrated minimal ATP binding by recombinant H1069Q ATP7B N-domain that did not saturate at 600 µM ATP, with at least three independent titrations per protein–nucleotide interaction (PMID:15205462). van Dijk et al. found approximately twofold weaker ATP affinity, reduced chemical and thermal stability, altered ATP-binding orientation, and increased structural flexibility in purified recombinant H1069Q N-domain (PMID:18692069). Tsivkovskii et al. reported reduced protein abundance without reduced transcript levels, endoplasmic-reticulum retention, and reduced copper-export capacity in transiently transfected cells; the cellular phenotype was partially temperature- and chaperone-responsive, supporting a folding/localization defect rather than an assay artifact (PMID:19937698). Besse et al. further reported impaired ATP binding, failure to form the catalytic phosphointermediate, reduced cellular protein abundance, and endoplasmic-reticulum localization with full-length ATP7B in HEK293 cells (PMID:21398519). These concordant results affect ATP binding, catalytic function, protein stability, localization, and copper export, all biologically relevant to ATP7B function. The studies are not described as validated clinical diagnostic-laboratory assays, so the evidence supports the ACMG/AMP strong category but not a higher-than-strong interpretation.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
PS4 is met. PMID:11857545 reports the exact H1069Q variant, NM_000053.4:c.3207C>A (p.His1069Gln), in 27 of 42 affected Wilson disease patients (64.3%). The paper does not provide an unaffected control cohort, so I performed the permitted comparison against the matched-ancestry gnomAD v4.1 NFE frequency: 1,249/1,180,030 alleles (0.1058%). Using the reported case frequency and the gnomAD NFE frequency as the comparison proportions, the odds ratio is 1,698.8 with an approximate 95% CI of 901.5-3,201.2. The governing ACMG/AMP comparison is OR >5.0 with a confidence interval that does not include 1.0; explicitly, 1,698.8 > 5.0? yes, and 901.5-3,201.2 excludes 1.0? yes. The control comparison is ancestry-proximate rather than a study-matched control cohort, so human review is retained.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
This is a missense variant, NM_000053.4:c.3207C>A (p.His1069Gln), so the generic PP3 missense path uses REVEL only. REVEL is 0.909, meeting the supplied PP3 supporting threshold of >=0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for a missense PP3 assessment, and the BayesDel score is not available for generic ACMG strength calibration.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PM2 is not met because the variant is present above the generic PM2 supporting threshold of 0.0001. The default all-comers sources apply because no VCEP or governing rule specifies a non-cancer or exome-only source. gnomAD v4.1 reports AF 0.000943521 (1,523/1,614,166 alleles) with one homozygote, and gnomAD v2.1 reports AF 0.00101864 (286/280,766 alleles) with zero homozygotes. These observations are not absent or at an extremely low frequency under the supplied threshold.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
PP5 is not met under the specified generic rule. ClinVar reports the exact variant as Pathogenic, but the record has no expert-panel submission; it consists of clinical-laboratory and other non-expert assertions. The literature reports of H1069Q are not a substitute for the required exact-variant ClinVar expert-panel classification, so PP5 is not applied.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
BA1 is not met. The required filtering frequency is the gnomAD grpmax FAF, not the population point estimate. In gnomAD v4.1, grpmax FAF is 0.0010095 (0.10095%), based on the Ashkenazi Jewish group with 29,608 observed alleles; this is below the generic BA1 threshold of 0.05 (5%). gnomAD v2.1 likewise reports grpmax FAF 0.00258435, below 0.05. The Ashkenazi Jewish point estimate of 0.00526885 is also below 5%, and no population-frequency basis supports a stand-alone benign call.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the supplied generic frequency rule. The appropriate filtering frequency is gnomAD grpmax FAF: 0.0010095 in gnomAD v4.1, with 29,608 observed Ashkenazi Jewish alleles, and 0.00258435 in gnomAD v2.1; both are below the generic 0.01 threshold. The variant is a well-documented Wilson disease allele with a consistent pathogenic ClinVar consensus, and the elevated ancestry-specific point estimate is not a valid substitute for FAF. No maximum-credible-frequency calculation is needed to reject the default BS1 frequency threshold because the filtering FAF itself is below 1%.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The directly studied H1069Q variant consistently produced damaging rather than normal functional results: minimal or reduced ATP binding, reduced stability, impaired catalytic-phosphointermediate formation, reduced protein abundance, endoplasmic-reticulum retention, and reduced copper export. No well-established assay in the reviewed evidence showed that H1069Q has no damaging effect on ATP7B protein function or splicing. The cellular rescue observed under low-temperature or pharmacological-chaperone conditions does not demonstrate normal baseline function and therefore does not support BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available ATP7B mutation-spectrum report identified 11 small insertions/deletions, seven missense mutations, two nonsense mutations, and three splice-site mutations among the reported mutations. This does not support a gene in which disease is caused primarily by truncating variants; missense disease variants are substantial and the cited series does not show truncating predominance.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The available affected-patient report describes homozygous and compound-heterozygous, rather than cis, observations for p.His1069Gln. ATP7B Wilson disease is recessive, so a trans observation does not satisfy the BP2 branch restricted to a fully penetrant dominant gene/disorder, and no cis observation with a pathogenic variant is documented.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
This is a missense variant, NM_000053.4:c.3207C>A (p.His1069Gln), so the generic BP4 missense path uses REVEL only. REVEL is 0.909, which does not meet the supplied BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not substituted for a gray-zone or non-benign REVEL result and is not used for a missense BP4 assessment; BayesDel is not available for generic ACMG strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP6 is not met. ClinVar does not provide an exact-variant expert-panel classification of Benign or Likely benign; the exact variant is reported as Pathogenic, with 0 expert-panel submissions. Ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
The variant is NP_000044.2:p.(His1069Gln), and ClinVar reports the exact NM_000053.4:c.3207C>A variant as Pathogenic. However, the available case evidence does not establish a previously pathogenic variant producing the same His1069Gln amino-acid change through a different nucleotide change. The exact alternate-nucleotide comparator required for PS1 is therefore missing.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No case-specific evidence documents a de novo occurrence of NM_000053.4:c.3207C>A (ATP7B p.His1069Gln), and there is no documentation of confirmed maternity and paternity, absence of family history, or a qualifying affected proband record for this criterion. The available literature reports affected individuals with the variant but does not establish de novo status or parental testing.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
ATP7B has no VCEP domain table in this case. Functional studies place His1069 within the ATP7B nucleotide-binding N-domain: the recombinant domain studied spans residues Val-1036–Asp-1196, and His1069 is reported to play an important role in nucleotide binding. This supports a well-established functional domain, but the required absence of benign variation in the relevant domain has not been demonstrated by the supplied evidence, so PM1 cannot be adjudicated.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
ATP7B-related Wilson disease is recessive. PMID:11857545 reports ATP7B p.His1069Gln (c.3207C>A) in 27 affected patients, including 18 described as compound heterozygous; two reported partner combinations were H1069Q/P969Q and H1069Q/3400delC. This is suggestive of occurrence with a second allele in affected probands, but the available extraction does not document parental or offspring testing establishing phase, and it does not independently establish P969Q or 3400delC as pathogenic. Therefore the required PM3 evidence cannot be confirmed from the available record.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The queried variant changes His1069 to Gln and is established as pathogenic in ClinVar. The supplied evidence does not identify a different missense substitution at residue 1069 that has independently been determined to be pathogenic. The same-residue pathogenic comparator required for PM5 is therefore unavailable.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-specific evidence documents an assumed de novo occurrence of NM_000053.4:c.3207C>A (ATP7B p.His1069Gln). The available literature reports affected individuals with the variant but does not identify an apparently de novo case or provide parental testing information.
Assumed de novo, but without confirmation of paternity and maternity.
The available variant-specific study reports H1069Q in 27 of 42 affected Wilson disease patients from 39 families, including nine homozygous and 18 compound-heterozygous patients, but it does not report transmission through pedigrees, affected relatives carrying the variant, or a count of informative meioses. Affected-case occurrence alone is not sufficient to establish co-segregation in multiple affected family members.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The case evidence documents pathogenic ATP7B missense variants, including p.His1069Gln, but does not provide a gene-level assessment establishing both a low rate of benign missense variation and missense variants as a common disease mechanism. A single variant frequency and disease-case reports cannot satisfy both PP2 requirements.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence identifies the disease context as Wilson disease but does not provide the phenotype or family history of the patient being adjudicated. Therefore, the required assessment of whether that patient's phenotype is highly specific for a disease with a single genetic etiology cannot be completed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available population record. gnomAD v4.1 reports one homozygote and gnomAD v2.1 reports zero homozygotes, but the gnomAD record does not establish that the individual was a healthy adult, provide age or phenotype information, or demonstrate the full early-age penetrance assumption required by the criterion. The single homozygote therefore cannot be treated as a qualifying healthy-adult observation.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No case-specific evidence documents affected family members who lack NM_000053.4:c.3207C>A (ATP7B p.His1069Gln), and no pedigree or non-segregation analysis is available. The reported affected cohort does not provide the unaffected-carrier or affected-noncarrier family data needed to evaluate lack of segregation.
Lack of segregation in affected members of a family.
No evidence in the supplied case materials establishes that this exact variant was found in a case with an alternate molecular basis for disease. A report of a different ATP7B variant in a patient with other genomic findings does not establish BP5 for NM_000053.4:c.3207C>A.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000053.4:c.3207C>A in ATP7B is a missense substitution predicted to produce NP_000044.2:p.(His1069Gln). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for ATP7B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000053.4:c.3207C>A in ATP7B is a missense substitution predicted to produce NP_000044.2:p.(His1069Gln). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for ATP7B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000053.4:c.3207C>A in ATP7B is a missense substitution predicted to produce NP_000044.2:p.(His1069Gln). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for ATP7B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000053.4:c.3207C>A in ATP7B is a missense substitution predicted to produce NP_000044.2:p.(His1069Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ATP7B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in ATP7B, mapped onto the exon structure of NM_000053.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish156 / 29,608 | 0.0053 |
| European (non-Finnish)1249 / 1,180,030 | 0.00111 hom |
| Remaining individuals58 / 62,508 | 0.00093 |
| European (Finnish)32 / 64,020 | 0.0005 |
| Admixed American25 / 60,020 | 0.00042 |
| African/African American3 / 75,046 | 4e-05 |
| Ashkenazi Jewish55 / 10,356 | 0.0053 |
| European (non-Finnish)196 / 128,580 | 0.0015 |
| Remaining individuals6 / 7,148 | 0.00084 |
| Admixed American17 / 35,364 | 0.00048 |
| European (Finnish)11 / 25,016 | 0.00044 |
| African/African American1 / 24,174 | 4.1e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000943521; MAF= 0.09435%, 1523/1614166 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00526885; MAF= 0.52688%, 156/29608 alleles, homozygotes = 0); grpmax FAF= 0.0010095.
This variant is present in gnomAD v2.1 (AF= 0.00101864; MAF= 0.10186%, 286/280766 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00531093; MAF= 0.53109%, 55/10356 alleles, homozygotes = 0); grpmax FAF= 0.00258435.
Not available in gnomAD-Canada v1.0.
This is a missense variant, NM_000053.4:c.3207C>A (p.His1069Gln), so the generic PP3 missense path uses REVEL only. REVEL is 0.909, meeting the supplied PP3 supporting threshold of >=0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for a missense PP3 assessment, and the BayesDel score is not available for generic ACMG strength calibration.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
This is a missense variant, NM_000053.4:c.3207C>A (p.His1069Gln), so the generic BP4 missense path uses REVEL only. REVEL is 0.909, which does not meet the supplied BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not substituted for a gray-zone or non-benign REVEL result and is not used for a missense BP4 assessment; BayesDel is not available for generic ACMG strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000053.4:c.3207C>A in ATP7B is a missense substitution predicted to produce NP_000044.2:p.(His1069Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ATP7B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.909. BayesDel score = 0.543887.
12 paper records listed. 5 cited in the classification.
The H1069Q mutation was found in 27 patients (64.3%). Nine patients were H1069Q homozygous.
Location Abstract
Context Cohort of 42 Wilson disease patients from 39 Hungarian families; H1069Q assessed by seminested PCR-based restriction fragment length polymorphism, other exon mutations identified by sequencing, and haplotype analysis performed using three microsatellite markers.
However, both mutations had a marked effect on nucleotide binding. As shown in Fig. 5B and Table II, E1064A lost the ability to bind ATP entirely, whereas the H1069Q mutant showed minimal binding, which did not reach saturation under the final conditions of our assay (i.e. at 600 µM ATP).
Location Results, “Residues Glu-1064 and His-1069 Play Important Roles in Nucleotide Binding,” paragraph 2; Fig. 5 and Table II
Context Site-directed mutagenesis of recombinant ATP7B nucleotide-binding domain residues Val-1036–Asp-1196, with circular dichroism spectroscopy and isothermal titration calorimetry at 25 °C.
The mutant has only twofold lower ATP affinity compared to that of the wild-type N-domain.
Location Abstract; Results and Discussion, “Affinity of WT for ATP and H1069Q Wilson disease N-domains”; Table 1; Conclusions
Context Purified recombinant ATP7B nucleotide-binding domains assessed by fluorescence ATP titration, unfolding assays, differential scanning calorimetry, and molecular-dynamics simulations.
H1069 is predicted to be involved in ATP binding, and p.H1069Q abolishes this interaction.
Location Results: “Homology Modeling Reveals Conformational Changes in ATP7B” (Fig. 3C); “Reduced Copper Export Capacity of ATP7B” (Fig. 5B-D); “Recovery of ATP7B Protein Expression by Low Temperature and Pharmacological Folding Chaperone Treatment” (Figs. 6-7); Table 1
Context HEK293T transient-expression protein-expression, copper-export, interaction, cell-surface, and chaperone-treatment assays, plus U2OS immunofluorescence localization; conditions included 30 °C culture, 4-phenylbutyrate, and curcumin.
This is in a contrast to the H1069Q mutation within the same β-HH, which greatly destabilizes protein both in vitro and in cells.
Location Abstract; Results sections “E1069A and H1069Q Mutants Show Marked Difference in Cellular Protein Levels” and “Differences in the N-domain Stability Correlate with the Intracellular Properties of E1064A and H1069Q Mutants”; Discussion
Context Recombinant ATP7B N-domain NMR and thermal-denaturation studies; full-length GFP-tagged ATP7B expression, confocal localization, Western blotting, and quantitative real-time PCR in HEK293TRex cells at 28 °C and 37 °C.
11 small insertions and deletions, seven missense, two nonsense and three splice site mutations
Abstract
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000943521; MAF= 0.09435%, 1523/1614166 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00526885; MAF= 0.52688%, 156/29608 alleles, homozygotes = 0); grpmax FAF= 0.0010095.
This variant is present in gnomAD v2.1 (AF= 0.00101864; MAF= 0.10186%, 286/280766 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00531093; MAF= 0.53109%, 55/10356 alleles, homozygotes = 0); grpmax FAF= 0.00258435.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (41 clinical laboratories). (ClinVarID = 3848)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.909. BayesDel score = 0.543887.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.