ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.3191A>C (p.Glu1064Ala) (rs374094065)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411652 SCV000485284 likely pathogenic Wilson disease 2016-11-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411652 SCV000915635 likely pathogenic Wilson disease 2017-10-20 criteria provided, single submitter clinical testing The ATP7B c.3191A>C (p.Glu1064Ala) missense variant has been reported in three studies in which it was found in a total of four individuals affected with Wilson disease, including in three in a compound heterozygous state (two of whom were siblings and carried the most common pathogenic variant associated with Wilson disease, p.His1069Gln, in trans) and in one with unknown zygosity (Shah et al. 1997; Kalinsky et al. 1998; Ala et al. 2005). The p.Glu1064Ala variant was present in a heterozygous state in 1/200 control chromosomes and is reported at a frequency of 0.00325 in the Ashkenazi Jewish population of the Genome Aggregation Database (Kalinsky et al. 1998). The variant occurs at a residue that is highly conserved across P1-ATPases in the helical hairpin region of the N-terminal domain, close to the most common pathogenic variant associated with Wilson disease. The p.Glu1064Ala variant has been shown to result in loss of ATP and ADP binding (Morgan et al. 2004; Dmitriev et al. 2011). In vivo structural NMR studies showed that the variant did not affect the overall fold of the N-domain containing the variant but did produce a more open structure which caused misalignment of ATP-binding residues which may account for the loss of ATP binding ability. In contrast, the p.Glu1064Ala variant did not affect stability or targeting of the protein in HEK293TRex cells (Dmitriev et al. 2011). However, based on the evidence, the p.Glu1064Ala variant is classified as a likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000411652 SCV000694439 pathogenic Wilson disease 2017-08-28 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.3191A>C (p.Glu1064Ala) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the HAD-like and cytoplasmic P-type ATPase domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 17/122090 control chromosomes at a frequency of 0.0001392, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been previously reported in patients with Wilsons disease (Kalinsky_1998, Ala_2005, Kuppala_2009 and Coffey_2013). In three affected individuals, this variant has been found in trans with another previously established deleterious variant in this gene (p.His1069Glu). Functional studies of this variant are consistent with loss of function of the mutant protein (Morgan_2004, Dmitriev_2011). In addition, one clinical diagnostic laboratory and one reputable database have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.

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