ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.2519C>T (p.Pro840Leu) (rs768671894)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169233 SCV000220503 likely pathogenic Wilson disease 2014-07-11 criteria provided, single submitter literature only
GeneDx RCV000333003 SCV000329796 pathogenic not provided 2016-03-15 criteria provided, single submitter clinical testing The P840L pathogenic variant in the ATP7B gene has been reported previously in several individuals with Wilson disease (Loudiano et al., 1998; Huster et al., 2012; Gu et al., 2013). This variant was not observed in approximately 6300 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 P840L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In-silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies demonstrate that the P840L variant results in impaired copper uptake (Huster et al., 2012). Missense variants in nearby residues (G836E, D842N, D842Y, G843R) have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P840L as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000169233 SCV000694424 pathogenic Wilson disease 2016-09-22 criteria provided, single submitter clinical testing Variant summary: The variant of interest affects a conserved nucleotide and results in replacing a small and kink-inducing Proline residue with a bulky and hydrophobic Leucine. 5/5 in silico prediction tools predict deleterious outcome by this substitution. The variant was found in the broad and large cohort of ExAC at an allele frequency of 1/120734 (0.0008%), which does not exceed the maximal expected allele frequency of a disease causing ATP7B allele (0.54%), further supporting a pathogenic nature for the variant. In addition, there are several Wilsons Disease patients reported to have the variant in compound heterozygote module (Amson_2012, Gu_2013, Nicastro_2010). Independent functional studies have shown that the variant results in the impairment of cellular copper transfer (Huster_2012 , Schushan_2012), which is consistent with a disease causing outcome. Considering all evidence, the variant was classified as pathogenic.

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