ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2294A>G (p.Asp765Gly) (rs1555291147)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589178 SCV000694417 pathogenic Wilson disease 2016-04-08 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2294A>G variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was not observed in controls (1000 Gs, ESP, or ExAC). Multiple publications cite the variant in affected individuals and authors indicate the variant is located in the predicted transmembrane helical hairpin N-terminal to the transduction domain, therefore it is predicted to be important for proper protein function (Gu_2003). Multiple publications and a database cite the variant to be "pathogenic/disease variant." In addition, another variant affecting this amino acid, c.2293G>A, p.Asp765Asn has been reported as a pathogenic variant. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000589178 SCV000960356 likely pathogenic Wilson disease 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 765 of the ATP7B protein (p.Asp765Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ATP7B variant in an individual affected with Wilson disease (PMID: 23843956). ClinVar contains an entry for this variant (Variation ID: 495406). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp765 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21682854, 15024742, 9482578, 20517649), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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