ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2071G>A (p.Gly691Arg)

dbSNP: rs121908001
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004070 SCV000220735 likely pathogenic Wilson disease 2014-09-24 criteria provided, single submitter literature only
Invitae RCV000004070 SCV001389674 pathogenic Wilson disease 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 691 of the ATP7B protein (p.Gly691Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 9671269, 17718866, 23389864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3866). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000004070 SCV001977355 likely pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004070 SCV002819939 pathogenic Wilson disease 2022-12-05 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2071G>A (p.Gly691Arg) results in a non-conservative amino acid change located in the TM2 domain (Loudianos_1998) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249376 control chromosomes (gnomAD and publication data). c.2071G>A has been reported in the literature in multiple individuals affected with Wilson Disease, including homozygotes (Loudianos_1998, Barada_2007, Couchonnal_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000004070 SCV004216454 pathogenic Wilson disease 2023-03-16 criteria provided, single submitter clinical testing
OMIM RCV000004070 SCV000024236 pathogenic Wilson disease 2007-09-01 no assertion criteria provided literature only
Natera, Inc. RCV000004070 SCV002087854 pathogenic Wilson disease 2021-02-17 no assertion criteria provided clinical testing

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