ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.3809A>G (rs121907990)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000004063 SCV000192352 pathogenic Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000004063 SCV000626859 pathogenic Wilson disease 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1270 of the ATP7B protein (p.Asn1270Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs121907990, ExAC 0.03%). This variant has been reported in multiple individuals as homozygous or in combination with other ATP7B variants in individuals affected with Wilson disease and there is evidence of disease co-segregation in a family (PMID: 27398169, 26269689, 20485189). ClinVar contains an entry for this variant (Variation ID: 3859). Experimental studies have shown that this variant results in a loss of copper transport function in vitro (PMID: 9654149, 22240481). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595271 SCV000700721 pathogenic not provided 2016-11-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004063 SCV000918603 pathogenic Wilson disease 2018-07-02 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3809A>G (p.Asn1270Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 120980 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.3809A>G has been reported in the literature in numerous individuals affected with Wilson Disease as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence on the variant and showed that copper uptake and transport are both defective (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000004063 SCV001157792 pathogenic Wilson disease 2018-08-03 criteria provided, single submitter clinical testing The ATP7B c.3809A>G; p.Asn1270Ser variant (rs121907990) is reported in the literature in numerous individuals affected with Wilson's disease (Abuduxikuer 2015, Barada 2010, Daneshjoo 2018, Guggilla 2015, Hua 2016, Tanzi 1993, Todorov 2005, Wu 1999). It has been reported to cosegregate with disease in families, both in the homozygous state (Barada 2010, Tanzi 1993) and in trans to another pathogenic variant (Daneshjoo 2018). The asparagine at codon 1270 is highly conserved, it occurs in the well-conserved hinge region of the ATP7B ATPase domain (Tanzi 1993), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Biochemical analyses indicate this variant has severely reduced copper transport activity (Huster 2012), and it fails to rescue growth defects of ccc2 mutant yeast to the extent of wildtype protein (Iida 1998). Other variants at this codon (p.Asn1270Asp, p.Asn1270Ile) are reported in Wilson's disease patients, though their pathogenicity has not yet been fully demonstrated (Nemeth 2016, Tuan Pham 2017). The p.Asn1270Ser variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3859), and it is found in the general population with an overall allele frequency of 0.18% (52/277208 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Abuduxikuer K et al. Wilson disease with hepatic presentation in an eight-month-old boy. World J Gastroenterol. 2015 Aug 7;21(29):8981-4. Barada K et al. Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. J Clin Gastroenterol. 2010 Jul;44(6):432-9. Daneshjoo O and Garshasbi M. Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report. J Med Case Rep. 2018 Mar 15;12(1):68. Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Iida M et al. Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae. FEBS Lett. 1998 May 29;428(3):281-5. Nemeth D et al. Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease. Gastroenterol Res Pract. 2016;2016:4548039. Tanzi RE et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 Dec;5(4):344-50. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. Tuan Pham LA et al. Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. J Genet. 2017 Dec;96(6):933-939. Wu Z et al. Missense mutations of exons 14 and 18 of Wilson's disease gene in Chinese patients. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 1999 Apr;16(2):91-3.
Myriad Women's Health, Inc. RCV000004063 SCV001194119 pathogenic Wilson disease 2020-01-03 criteria provided, single submitter clinical testing NM_000053.3(ATP7B):c.3809A>G(N1270S) is classified as pathogenic in the context of Wilson Disease. Sources cited for classification include the following: PMID 23518715, 12544487, 22240481, 10790207, 9452121, 9829905, 19419418, 9311736, 7626145 and 9654149. Classification of NM_000053.3(ATP7B):c.3809A>G(N1270S) 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 RCV000595271 SCV001247791 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
OMIM RCV000004063 SCV000024229 pathogenic Wilson disease 2009-04-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000004063 SCV000190069 pathogenic Wilson disease 2014-06-01 no assertion criteria provided research

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