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

dbSNP: rs1057520235

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667536	SCV003442177	pathogenic	Wilson disease	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 857 of the ATP7B protein (p.Ile857Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 8533760, 14974157, 17317524). This variant is also known as Ileu858Thr. ClinVar contains an entry for this variant (Variation ID: 377538). 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: 22240481). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000667536	SCV000792005	likely pathogenic	Wilson disease	2017-06-06	no assertion criteria provided	clinical testing