Submissions for variant NM_000053.4(ATP7B):c.2939G>A (p.Cys980Tyr)

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Total submissions: 7

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672631	SCV000797755	likely pathogenic	Wilson disease	2018-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672631	SCV002766195	pathogenic	Wilson disease	2022-11-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2939G>A (p.Cys980Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249386 control chromosomes (gnomAD). c.2939G>A has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Wang_2011, Li_2013, Hui_2013, Wang_2018, Xiao_2021, Poon_2016, Mak_2008). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672631	SCV003442174	pathogenic	Wilson disease	2023-11-13	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 980 of the ATP7B protein (p.Cys980Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 24146181, 34324271). ClinVar contains an entry for this variant (Variation ID: 556603). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000672631	SCV003800515	likely pathogenic	Wilson disease	2022-04-01	criteria provided, single submitter	clinical testing	The ATP7B c.2939G>A; p.Cys980Tyr variant (rs1038582488) is reported in the literature in multiple individuals affected with Wilson disease, often found with a second pathogenic variant (Li 2013, Mak 2008, Xiao 2021). This variant is reported in ClinVar (Variation ID: 556603) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.2939G>T, p.Cys980Phe; c.2938T>C, p.Cys980Arg) have been reported in individuals with Wilson disease (Li 2019, Li 2013). The cysteine at codon 980 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.773). Based on available information, this variant is considered to be likely pathogenic. References: Li X et al. Clinical features and mutational analysis in 114 young children with Wilson disease from South China. Am J Med Genet A. 2019 Aug;179(8):1451-1458. PMID: 31172689. Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. PMID: 23235335. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. PMID: 18034201. Xiao Z et al. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med. 2021 Sep;9(9):e1735. PMID: 34324271.
PreventionGenetics, part of Exact Sciences	RCV003420191	SCV004114584	likely pathogenic	ATP7B-related disorder	2022-11-10	criteria provided, single submitter	clinical testing	The ATP7B c.2939G>A variant is predicted to result in the amino acid substitution p.Cys980Tyr. This variant was reported along with a known pathogenic variant (c.2333G>T, p.Arg778Leu) in an individual with Wilson disease (Fang et al. 2021. PubMed ID: 34002136). It has also been reported in other Wilson disease patients, although without additional functional or genetic evidence (for example, see Mak et al. 2007. PubMed ID: 18034201; Li et al. 2013. PubMed ID: 23235335; Poon et al. 2016. PubMed ID: 26483271; Wei et al. 2014. PubMed ID: 25089800). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52520541-C-T). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000672631	SCV004216386	pathogenic	Wilson disease	2023-07-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000672631	SCV004825451	uncertain significance	Wilson disease	2023-08-15	criteria provided, single submitter	clinical testing

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