ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3008C>T (p.Ala1003Val) (rs775055397)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169109 SCV000220309 likely pathogenic Wilson disease 2014-05-14 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169109 SCV001361702 pathogenic Wilson disease 2019-12-09 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3008C>T (p.Ala1003Val) 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 3.3e-05 in 240390 control chromosomes (gnomAD). c.3008C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Loudianos_1999, Coffey_2013, Guggilla_2015). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169109 SCV001592608 pathogenic Wilson disease 2020-02-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1003 of the ATP7B protein (p.Ala1003Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs775055397, ExAC 0.06%). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 31059521, 10544227, 17264425). ClinVar contains an entry for this variant (Variation ID: 188781). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Ala1003 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21610751, 12885331, 26799313, Invitae). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001508716 SCV001715051 likely pathogenic not provided 2020-09-04 criteria provided, single submitter clinical testing PS4_moderate, PM2, PM5, PP4
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000169109 SCV001469299 pathogenic Wilson disease 2020-10-11 no assertion criteria provided clinical testing

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