ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln) (rs121907996)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000270891 SCV000329795 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing The R969Q pathogenic variant in the ATP7B gene has been reported previously, using alternate nomenclature A970Q, in association with Wilson disease when present in the homozygous state or when in trans with another disease-causing variant (Figus et al., 1995). The R969Q variant was not observed in approximately 6,200 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 R969Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show R969Q had a significant decrease in copper uptake compared to wild type (Huster et al., 2012). Missense variants in the same and nearby residues (R969W, A971V, T974M) 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 R969Q as a pathogenic variant.
Counsyl RCV000004064 SCV000678091 pathogenic Wilson disease 2014-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004064 SCV000916622 pathogenic Wilson disease 2017-11-16 criteria provided, single submitter clinical testing Variant summary: Variant summary: The ATP7B c.2906G>A (p.Arg969Gln) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type_ATPase_Cu-like domain and 3/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional studies, where R969Q was shown to markedly affect copper transport and lead to hyperphosphorylation (Huster, 2012). This variant was found in 10/277242 control chromosomes at a frequency of 0.000036, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals with clinically and biochemically confirmed Wilsons disease (WD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000004064 SCV001229234 pathogenic Wilson disease 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 969 of the ATP7B protein (p.Arg969Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121907996, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another ATP7B variant in multiple individuals affected with Wilson disease (PMID: 8533760, 20517649, 22308153, 26819605, 17325640, 9801873). This variant is also known as p.Arg970Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 3860). This variant has been reported to have conflicting or insufficient data to determine the effect on ATP7B protein function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004064 SCV000024230 pathogenic Wilson disease 2004-12-01 no assertion criteria provided literature only

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