13-51944145-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000242839.10(ATP7B):c.3207C>A(p.His1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. 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. H1069R) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00094 ( 1 hom. )
Consequence
ATP7B
ENST00000242839.10 missense
ENST00000242839.10 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 2.73
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 18 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000242839.10
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-51944146-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1069926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948
PP5
Variant 13-51944145-G-T is Pathogenic according to our data. Variant chr13-51944145-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51944145-G-T is described in Lovd as [Pathogenic]. Variant chr13-51944145-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3207C>A | p.His1069Gln | missense_variant | 14/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP7B | ENST00000242839.10 | c.3207C>A | p.His1069Gln | missense_variant | 14/21 | 1 | NM_000053.4 | ENSP00000242839 | P1 |
Frequencies
GnomAD3 genomes 0.000933 AC: 142AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000922 AC: 230AN: 249392Hom.: 0 AF XY: 0.000850 AC XY: 115AN XY: 135356
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GnomAD4 genome 0.000932 AC: 142AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74464
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:37Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:28Other:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces histidine with glutamine at codon 1069 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 results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388). This variant has been reported in numerous homozygous and compound heterozygous individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9214248, 9352458, 9887381, 10051024, 10406672, 10544227, 11857545, 12557139, 15967699, 16207219, 18311837, 19306278, 22286624, 22221592, 22720308, 22730635, 23430908, 24897373, 26286547, 28776642, 30609409, 31708252, 32043565, 32270360, 32532207, 33098801) and has been shown to segregate with disease in family studies (PMID: 24897373, 31708252, 32043565, 32532207). Homozygosity for this variant is the most common cause of Wilson disease among patients of European ancestry (PMID: 7626145, 9724794, 9887381). This variant has been identified in 286/280766 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 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous missense variant, NM_000053.3(ATP7B):c.3207C>A, has been identified in exon 14 of 21 of the ATP7B gene. The variant is predicted to result in a minor amino acid change from histidine to glutamine at position 1069 of the protein (NP_000044.2(ATP7B):p.(His1069Gln)). The histidine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the ATP loop domain (Wilson Disease Mutation Database). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.1% (286 heterozygotes, 0 homozygotes). This variant has been previously described as pathogenic, and is one of the most common pathogenic alleles causing Wilsons disease (Kluska, A., et al. (2019), ClinVar, Wilson Disease Database). Additionally, functional studies of mutant protein disrupts intracelleular copper balance and reduced protein stability (Huster D. et al. (2003), Rodriguez-Granillo, A., et al. (2008)). An alternative change at the same codon to asparagine has also been reported in a patient with Wilson's disease (Zali, N., et al. (2011)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | This missense variant replaces histidine with glutamine at codon 1069 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 results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388). This variant has been reported in numerous homozygous and compound heterozygous individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9214248, 9352458, 9887381, 10051024, 10406672, 10544227, 11857545, 12557139, 15967699, 16207219, 18311837, 19306278, 22286624, 22221592, 22720308, 22730635, 23430908, 24897373, 26286547, 28776642, 30609409, 31708252, 32043565, 32270360, 32532207, 33098801) and has been shown to segregate with disease in family studies (PMID: 24897373, 31708252, 32043565, 32532207). Homozygosity for this variant is the most common cause of Wilson disease among patients of European ancestry (PMID: 7626145, 9724794, 9887381). This variant has been identified in 286/280766 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 22, 2023 | The ATP7B c.3207C>A; p.His1069Gln variant (rs76151636), also known as His714Gln, has been reported in the homozygous and compound heterozygous state in numerous individuals diagnosed with Wilson disease (Cocos 2014, Duc 1998, Tanzi 1993). Functional studies indicate that the variant protein has altered subcellular localization (Payne 1998, van den Berghe 2009), reduced affinity to ATP (Morgan 2004, Rodriguez-Granillo 2008) and reduced half-life (Payne 1998). Cells expressing the variant protein show reduced viability when exposed to increased levels of copper (Payne 1998). This variant is reported in ClinVar (Variation ID: 3848) and is found in the general population with an overall allele frequency of 0.10% (286/280766 alleles) in the Genome Aggregation Database. The histidine at codon 1069 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.909). Based on available information, this variant is considered to be pathogenic. References: Cocos R et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One. 2014 9(6):e98520. PMID: 24897373. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 6(6):616-23. PMID: 9887381. Morgan C et al. The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem. 2004 279(35):36363-71. PMID: 15205462. Payne AS et al. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci U S A. 1998 95(18):10854-9. PMID: 9724794. Rodriguez-Granillo A et al. Stability and ATP binding of the nucleotide-binding domain of the Wilson disease protein: effect of the common H1069Q mutation. J Mol Biol. 2008 383(5):1097-111. PMID: 18692069. Tanzi R et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 5(4):344-50. PMID: 8298641. van den Berghe P et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology. 2009 50(6):1783-95. PMID: 19937698. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Aug 31, 2022 | ACMG categories: PS3,PM1,PM2,PP3,PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1069 of the ATP7B protein (p.His1069Gln). This variant is present in population databases (rs76151636, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease. This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe and has been mainly associated in the homozygous state with a late onset course of the disease. (PMID: 8298641, 9887381, 18311837, 22221592, 22286624, 22720308, 24897373). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3848). 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: 9724794, 19937698, 22240481, 24909901). 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 | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 23, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.H1069Q in ATP7B (NM_000053.3) has been previously reported in affected individuals and is the most common variant in Central and Eastern European countries. It is submitted to the Clinvar database as Pathogenic. The p.H1069Q variant is observed in 54/10,066 (0.5365%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exome. The p.H1069Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 1069 of ATP7B is conserved in all mammalian species. The nucleotide c.3207 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.102%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.93). The the same nucleotide change resulting in the the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003848/PMID:8298641/3billion dataset). Different missense changes at the the same codon (p.His1069Arg, p.His1069Asn, p.His1069Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001069926/PMID: 21645214, 22308153). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 04, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | ATP7B NM_000053.3 exon 14 p.His1069Gln (c.3207C>A): This variant is one of the most common pathogenic variants in the ATP7B gene and has been reported in both the homozygous and compound heterozygous state in several individuals with Wilson disease (Tanzi 1993 PMID: 8298641, Duc 1998 PMID:9887381, Firneisz 2002 PMID:11857545). This variant is present in 0.1% (196/128580) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-52518281-G-T?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:3848). Evolutionary conservation and computational predictive tools support that this variant will impact the protein. In vivo and In vitro functional studies suggest that this variant reduces ATP binding and is retained in the endoplasmic reticulum (Morgan 2004 PMID:15205462, Mercer 2017 PMID:28119449, Parisi 2018 PMID:29674751). In summary, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000053.3:c.3207C>A in the ATP7B gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.His1069Gln had a very low activity comprared to wildtype (PMID: 22240481), resulted in reduced ATP7B protein expression (PMID: 19937698), and caused subcellular mislocalization (PMID: 24909901). This variant is the most common cause of Wilson disease in Eastern, Northern, and Central Europe, and was identified in mutiple compound heterozygous or homozygous, such as H1069Q/M769H (PMID: 24897373), H1069Q/H1069Q (PMID: 22720308), H1069Q/H1069Q (PMID: 22221592). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_000053.3(ATP7B):c.3207C>A(H1069Q) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9352458, 9887381, 11857545, and 7626145. Classification of NM_000053.3(ATP7B):c.3207C>A(H1069Q) 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 | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | Variant summary: ATP7B c.3207C>A (p.His1069Gln) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) 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 0.00092 in 249392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00092 vs 0.0054), allowing no conclusion about variant significance. c.3207C>A has been reported in the literature in numerous individuals affected with Wilson Disease (e.g., Cocos_2014, Gromadzka_2010, Loudianos_1999, Caca_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal nucleotide binding activity (e.g., Morgan_2004). The following publications have been ascertained in the context of this evaluation (PMID: 17717039, 10544227, 11690702, 15205462, 24897373, 21334398). ClinVar contains an entry for this variant (Variation ID: 3848). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 03-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2020 | The p.His1069Gln variant in ATP7B has been reported in numerous homozygous and compound heterozygous individuals with Wilson disease and is the most common variant identified in European patients (Tanzi 1993, Duc 1999, Ivanova-Smolenskaya 1999, Caca 2001, Cocos 2014). This variant has also been reported by clinical laboratories in ClinVar (Variation ID#3848) and been identified in 0.5% (53/10148) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is consistent with the known carrier frequency of Wilson disease. In vitro functional studies provide some evidence that the p.His1069Gln variant may result in reduced ATP7B protein expression (van den Berghe 2009) and computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease based upon its common biallelic occurrence in patients with this disease and functional evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Mar 07, 2014 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 08, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PP2,PP3,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 05, 2024 | Criteria applied: PM3_VSTR,PS3,PM5_STR,PM2_SUP,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 01, 2021 | ATP7B c.3207C>A has been identified in the homozygous or compound heterozygous state in many individuals with Wilson disease. It is the most common pathogenic ATP7B variant associated with Wilson disease in populations of European origin. This variant (rs76151636) is present in a large population dataset (gnomAD: 286/280766 total alleles; 0.1019%; no homozygotes) and has been reported in ClinVar. Functional studies demonstrate that this substitution results in mislocalization and increased degradation of the ATP7B protein in cells. We consider ATP7B c.3207C>A to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 17, 2017 | - - |
| Pathogenic, no assertion criteria provided | case-control | Genomics And Bioinformatics Analysis Resource, Columbia University | Apr 11, 2018 | - - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | ATP7B: PM3:Very Strong, PM1, PM5, PS3:Moderate, PM2:Supporting, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Aug 29, 2022 | PS4, PP3, PM2_SUP, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 22, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2019 | Published functional studies show the H1069Q variant has significantly reduced ATP binding affinity and reduced protein stability, leading to impaired copper transport (Dmitriev et al., 2011; Morgan et al., 2004; Rodriguez-Granillo et al., 2008; Chesi et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22692182, 25333069, 24897373, 22730635, 22240481, 28392828, 27641668, 28119449, 28776642, 30609409, 31028847, 28602929, 23430908, 19306278, 22286624, 30232804, 15024742, 23982005, 24253677, 24909901, 9887381, 9654149, 18692069, 22221592, 8298641, 11857545, 15967699, 27122662, 26660341, 18311837, 10406672, 19937698, 26286547, 16567646, 28717664, 23159873, 22763723, 18855987, 9724794, 29674751, 15205462, 21398519, 31708252, 31664448, 31980526, 32043565, 32532207) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2021 | The c.3207C>A (p.H1069Q) alteration is located in exon 14 (coding exon 14) of the ATP7B gene. This alteration results from a C to A substitution at nucleotide position 3207, causing the histidine (H) at amino acid position 1069 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.1% (286/280766) total alleles studied. The highest observed frequency was 0.53% (55/10356) of Ashkenazi Jewish alleles. The p.H1069Q alteration is the most common mutation found in Wilson disease. Thirteen homozygous individuals with Wilson disease were observed to present at a later age, have a high occurrence of hepatic disease, and display neurological symptoms more often than compound heterozygotes with a different mutation (Panagiotakaki, 2004). Another study showed that when compared to individuals with mutations other than p.H1069Q, those with p.H1069Q were less likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and more likely to have a neurologic phenotype (Usta, 2012). Another study of 7 homozygotes displayed a larger degree of phenotypic variability, although 4 individuals presented with neurological disease (Duc, 1998). This amino acid position is highly conserved in available vertebrate species. Based on several functional studies, this mutation affects ATP binding, protein dynamics, and chemical and thermal stabilities relative to wild type (Rodriguez-Granillo, 2008; Dmitriev, 2011; Morgan, 2004). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Pathogenic
D;D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;B;D;D;D
Vest4
MutPred
Gain of helix (P = 0.062);.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at