ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3272G>A (p.Cys1091Tyr) (rs778825095)

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Total submissions: 3
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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.
Integrated Genetics/Laboratory Corporation of America 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.

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