ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2570T>C (p.Ile857Thr) (rs1057520235)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430661 SCV000512210 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The I857T variant in the ATP7B gene has been reported previously in the homozygous state or in the heterozygous state with a second ATP7B variant in at least four individuals with Wilson disease, two of whom were described as having onset of neurologic symptoms in adulthood (Figus et al., 1995; Chappuis et al., 2007; Folhoffer et al., 2007). Note that alternate nomenclature I858T was used by Figus et al. (1995). Functional studies of the I857T variant indicate that it results in reduced but not absent copper transport activity, resulting in less copper accumulation than some other ATP7B variants (Huster et al., 2012). The I857T variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I857T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is well conserved across species. The I857T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000667536 SCV001158352 likely pathogenic Wilson disease 2019-04-05 criteria provided, single submitter clinical testing The ATP7B c.2570T>C; p.Ile857Thr variant (rs1057520235) is reported in the literature in individuals with Wilson disease in both the homozygous and compound heterozygous states (Chappuis 2007, Figus 1995 (reported as Ileu858Thr), Ferenci 2007, Folhoffer 2007). Additionally, functional analyses show the variant protein has decreased copper transport (Huster 2012). This variant is reported as likely pathogenic in ClinVar (Variation ID: 377538). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 857 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 likely pathogenic. REFERENCES Chappuis P et al. Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene. J Trace Elem Med Biol. 2007;21(1):37-42. Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995 Dec;57(6):1318-24. Ferenci P et al. Late-onset Wilson's disease. Gastroenterology. 2007 Apr;132(4):1294-8. Folhoffer A et al. Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. Eur J Gastroenterol Hepatol. 2007 Feb;19(2):105-11. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5.
Counsyl RCV000667536 SCV000792005 likely pathogenic Wilson disease 2017-06-06 no assertion criteria provided clinical testing

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