ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln) (rs76151636)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000004052 SCV000052016 pathogenic Wilson disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078049 SCV000225992 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000004052 SCV000236509 pathogenic Wilson disease 2014-03-07 criteria provided, single submitter clinical testing
GeneDx RCV000078049 SCV000329091 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The H1069Q pathogenic variant in the ATP7B gene has been reported previously in the homozygous and compoundheterozygous state, opposite of a second ATP7B variant, in patients with biochemically proven Wilson disease andassociated hepatic and neurologic abnormalities (Firneisz et al., 2002; Duc et al., 1998). The H1069Q variant is themost common pathogenic variant in Wilson disease patients from Central and Eastern European countries (Vrabelovaet al., 2005). Functional studies show the H1069Q variant has increased thermal liability and reduced ATP bindingaffinity compared to wild-type which adversely affects normal ATP7B enzyme function (Morgan et al., 2004;Rodriguez-Granillo et al., 2008). The H1069Q variant is a semi-conservative amino acid substitution and occurs at aposition that is conserved across species. We interpret H1069Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000004052 SCV000593529 pathogenic Wilson disease 2017-01-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000004052 SCV000602583 pathogenic Wilson disease 2018-08-07 criteria provided, single submitter clinical testing The ATP7B c.3207C>A; p.His1069Gln variant (rs76151636), also known as His714Gln, has been reported in numerous individuals diagnosed with Wilson's 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 as pathogenic in ClinVar (Variation ID: 3848). It is found in the general population with an overall allele frequency of 0.1% (286/280766 alleles) in the Genome Aggregation Database. The histidine at codon 1069 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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. 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. 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. Payne A 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. 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. 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. 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.
Fulgent Genetics,Fulgent Genetics RCV000004052 SCV000611174 pathogenic Wilson disease 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000004052 SCV000626851 pathogenic Wilson disease 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 1069 of the ATP7B protein (p.His1069Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs76151636, ExAC 0.2%). 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). ClinVar contains an entry for this variant (Variation ID: 3848). Experimental studies have shown that this missense change causes subcellular mislocalization of the ATP7B protein in the endoplasmic reticulum where it undergoes rapid degradation (PMID: 9724794, 19937698, 22240481, 24909901). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000004052 SCV000967653 pathogenic Wilson disease 2017-11-22 criteria provided, single submitter clinical testing The p.His1069Gln (NM_000053.3 c.3207C>A) variant in ATP7B has been reported in m any homozygous and compound heterozygous individuals with Wilson disease and is the most common variant identified in European patients (Tanzi 1993; Ha-Hao, 199 9; Ivanova-Smolenskaya 1999; Caca 2001; Cocos 2014). This variant has also been reported in ClinVar (Variation ID#3848). This variant has also been identified i n 0.5% (53/10148) of Ashkenazi Jewish chromosomes by Genome Aggregation Database (gnomAD, Http://gnomad.broadinstitute.org; dbSNP rs76151636). This frequency is consistent with the known carrier frequency of Wilson disease. In vitro functio nal studies provide some evidence that the p.His1069Gln variant may result in re duced ATP7B protein expression (van den Berghe 2009). In summary, this variant m eets criteria to be classified as pathogenic for Wilson disease in an autosomal recessive manner based upon its common biallelic occurrence in patients with thi s disease and functional evidence.
Institute of Human Genetics,Klinikum rechts der Isar RCV000004052 SCV001149696 pathogenic Wilson disease 2019-01-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000004052 SCV001163729 pathogenic Wilson disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004052 SCV001193833 pathogenic Wilson disease 2019-10-18 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078049 SCV001247795 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
OMIM RCV000004052 SCV000024218 pathogenic Wilson disease 2005-11-01 no assertion criteria provided literature only
GeneReviews RCV000004052 SCV000086653 pathologic Wilson disease 2013-05-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Myriad Women's Health, Inc. RCV000004052 SCV000485258 pathogenic Wilson disease 2016-03-11 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000004052 SCV000733357 pathogenic Wilson disease no assertion criteria provided clinical testing
Institute for Genomic Medicine, Columbia University,Columbia University Medical Center RCV000004052 SCV000778805 pathogenic Wilson disease 2018-04-11 no assertion criteria provided case-control
Reproductive Health Research and Development,BGI Genomics RCV000004052 SCV001142439 pathogenic Wilson disease 2020-01-06 no assertion criteria provided curation 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.

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