ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val) (rs121907994)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004055 SCV000487224 pathogenic Wilson disease 2016-10-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004055 SCV000916640 pathogenic Wilson disease 2018-11-16 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2621C>T (p.Ala874Val) results in a non-conservative amino acid change in the P-type ATPase, A domain superfamily of 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 6.9e-05 in 246236 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.2621C>T, has been reported in the literature in multiple individuals affected with Wilson Disease in both compound heterozygotes and homozygotes (Lee_2011, Dong_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function evaluating copper transport. The most pronounced variant effect results in 10-30% of normal copper transport rate activity (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000004055 SCV000626845 pathogenic Wilson disease 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 874 of the ATP7B protein (p.Ala874Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121907994, ExAC 0.07%). This variant has been reported as heterozygous co-occurring with another ATP7B variant, as well as homozygous, in multiple individuals with Wilson disease (PMID: 10721669, 10544227, 21707886, 11775208, 12544487, 16998622, 22735241), with evidence of co-segregation with disease (PMID: 12376745, 18156766). ClinVar contains an entry for this variant (Variation ID: 3851). Experimental studies have shown that this variant reduces the activity and stability of the encoded protein (PMID: 22692182, 22240481). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004055 SCV000024221 pathogenic Wilson disease 2009-04-01 no assertion criteria provided literature only
SingHealth Duke-NUS Institute of Precision Medicine RCV000004055 SCV000853123 likely pathogenic Wilson disease 2017-06-07 no assertion criteria provided curation
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000004055 SCV000267218 uncertain significance Wilson disease 2016-03-18 criteria provided, single submitter reference population

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