ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3191A>C (p.Glu1064Ala) (rs374094065)

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Total submissions: 5
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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
Integrated Genetics/Laboratory Corporation of America RCV000411652 SCV000694439 pathogenic Wilson disease 2019-05-08 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3191A>C (p.Glu1064Ala) 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 0.00015 in 251578 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. This variant has been previously reported in patients with Wilson's disease (Kalinsky_1998, Ala_2005, Perri_2005, Kuppala_2009, and Coffey_2013). In four of these affected individuals, this variant has been found in trans with another previously established deleterious variant in the same gene (p.His1069Glu). These data indicate that the variant is likely to be associated with disease. Functional studies suggest that this missense change disrupts the protein's ability to bind ATP completely which is consistent with the loss of function of the mutant protein (Morgan_2004, Dmitriev_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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.
Invitae RCV000411652 SCV000954221 pathogenic Wilson disease 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1064 of the ATP7B protein (p.Glu1064Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs374094065, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with Wilson disease (PMID: 2610069). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 370081). Experimental studies have shown that this missense change disrupts the ATP binding function of the ATP7B protein (PMID: 15205462). Variants that disrupt the p.Glu1064 amino acid residue in ATP7B have been observed in affected individuals (PMID: 15723329, 17272994). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000411652 SCV000966822 likely pathogenic Wilson disease 2018-10-05 criteria provided, single submitter clinical testing The p.Glu1064Ala variant in ATP7B has been reported in the compound heterozygous state with the p.His1069Gln variant in 3 individuals with Wilson disease, inclu ding at least 2 with mild disease, and segregated with disease in one affected r elative (Ala 2005, Perri 2005, Coffey 2013). This variant has been identified in 0.33% (32/9846) of Ashkenazi Jewish chromosomes and 4/111606 European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ) and is reported in ClinVar (Variation ID:370081). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evi dence that the p.Glu1064Ala variant may impact protein function (Morgan 2004, Di mitriev 2011, Schushan 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation a nalysis suggest that the p.Glu1064Ala variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. Additionally, another variant at the same residue, p.Glu1061Lys, has been identified in patie nts with Wilson disease, suggesting variation at this site may not be tolerated. In summary, although additional studies are required to fully establish its cli nical significance, the p.Glu1064Ala variant is likely pathogenic. ACMG/AMP crit eria applied: PM3_Strong, PM5, PS3_Moderate, PP3.

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