Submissions for variant NM_000053.4(ATP7B):c.3272G>A (p.Cys1091Tyr)

dbSNP: rs778825095

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668718	SCV000793363	uncertain significance	Wilson disease	2017-08-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757021	SCV000885046	likely pathogenic	not provided	2017-11-10	criteria provided, single submitter	clinical testing	The ATP7B c.3272G>A; p.Cys1091Tyr variant is published in the medical literature in at least one individual with Wilson disease (Park 2007). Additionally, ARUP laboratories has detected this variant in an individual with Wilson disease who also carried a frameshift variant on the opposite chromosome. Another variant in the same codon, p.Cys1091Arg, is also published in the medical literature in an individual with suspected Wilson disease (Dong 2016). The p.Cys1091Tyr variant is not listed in the ClinVar database, but is listed in the dbSNP variant database (rs778825095), and in the Genomics Aggregation Database in 1/246220 alleles. The cysteine at codon 1091 is moderately conserved across species, occurs in the N domain important for ATP binding (Hercend 2011, Morgan 2004), and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. Hercend C et al. Elucidation of the ATP7B N-domain Mg2+-ATP coordination site and its allosteric regulation. PLoS One. 2011;6(10):e26245. Morgan CT 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 Aug 27;279(35):36363-71. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779813	SCV000916627	uncertain significance	not specified	2017-12-08	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.3272G>A (p.Cys1091Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/246320 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in one Wilson disease patient in the literature as a compound heterozygous allele (Park_2007). This study also performed complementation assays that showed the variant reduced yeast growth compared to controls, suggesting normal function is impaired. Taken together, this variant is classified as VUS-possibly pathogenic.
Genome-Nilou Lab	RCV000668718	SCV001977134	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV000668718	SCV003442232	uncertain significance	Wilson disease	2022-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1091 of the ATP7B protein (p.Cys1091Tyr). This variant is present in population databases (rs778825095, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17587212). ClinVar contains an entry for this variant (Variation ID: 553303). 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. Experimental studies have shown that this missense change affects ATP7B function (PMID: 17587212). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002531207	SCV003595200	uncertain significance	Inborn genetic diseases	2021-12-08	criteria provided, single submitter	clinical testing	The c.3272G>A (p.C1091Y) alteration is located in exon 15 (coding exon 15) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 3272, causing the cysteine (C) at amino acid position 1091 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/249554) total alleles studied. The highest observed frequency was <0.01% (1/34524) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.