ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2828G>A (p.Gly943Asp) (rs779323689)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169455 SCV000220876 likely pathogenic Wilson disease 2014-11-13 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169455 SCV000694433 pathogenic Wilson disease 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2828G>A (p.Gly943Asp) variant located in the P-type ATPase, A domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120380 (1/60190), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/185. Multiple publications have cited the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169455 SCV001580163 pathogenic Wilson disease 2020-01-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 943 of the ATP7B protein (p.Gly943Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs779323689, ExAC 0.02%). This variant has been observed in individual(s) with WIlson disease (PMID: 16603785, 27930511). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189058). 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: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Gly943 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7626145, 11243728, 27022412, 10942420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531800 SCV001747087 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing

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