ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3659C>T (p.Thr1220Met) (rs193922107)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029374 SCV000052022 pathogenic Wilson disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Counsyl RCV000029374 SCV000220459 likely pathogenic Wilson disease 2014-06-29 criteria provided, single submitter literature only
GeneDx RCV000413521 SCV000491163 pathogenic not provided 2016-11-11 criteria provided, single submitter clinical testing The T1220M missense variant in the ATP7B gene has been reported multiple times in patients with Wilson disease (Loudianos et al. 1996; Gromadzka et al. 2005; Lepori et al. 2007; Wan et al. 2010; Møller et al. 2011; Hofer et al. 2012; Chabik et al. 2014). The Threonine at position 1220 is the first residue of the ATP-binding domain of the ATP7B protein (Loudianos et al. 1996). Site-directed mutagenesis of the residues in the ATP-binding domain found that alteration of this sequence abolishes calcium transport activity (Loudianos et al. 1996). The T1220M variant was not observed in approximately 6500 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 T1220M 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 conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000029374 SCV000611172 likely pathogenic Wilson disease 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000029374 SCV000940902 pathogenic Wilson disease 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1220 of the ATP7B protein (p.Thr1220Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 25497208, 22763723, 21610751, 24661374, Invitae). ClinVar contains an entry for this variant (Variation ID: 35725). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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