ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1846C>T (p.Arg616Trp)

gnomAD frequency: 0.00001  dbSNP: rs374172791
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001069979 SCV001235184 pathogenic Wilson disease 2023-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 616 of the ATP7B protein (p.Arg616Trp). This variant is present in population databases (rs374172791, gnomAD 0.004%). This missense change has been observed in individuals with Wilson disease (PMID: 11690702, 28507923). ClinVar contains an entry for this variant (Variation ID: 863093). 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%. This variant disrupts the p.Arg616 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12885331, 21610751, 22735241, 26799313). 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 RCV001508349 SCV001714456 pathogenic not provided 2022-09-07 criteria provided, single submitter clinical testing PP3, PP4, PM2, PM5, PS3
Genome-Nilou Lab RCV001069979 SCV001977362 likely pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001069979 SCV002570338 likely pathogenic Wilson disease 2022-09-02 criteria provided, single submitter clinical testing This ATP7B variant (rs374172791) is rare (<0.1%) in a large population dataset (gnomAD: 4/249570 total alleles; 0.0016%; no homozygotes) and has been reported in ClinVar. A different pathogenic missense change affecting the same amino acid, c.1847G>A (p.Arg616Gln), has also been reported. Two bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 5 splicing, although this has not been confirmed experimentally to our knowledge. This variant has been reported in the literature in a homozygous or compound heterozygous state in individuals with WND. We consider c.1846C>T to be likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001069979 SCV002810411 likely pathogenic Wilson disease 2022-01-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV001069979 SCV004216286 likely pathogenic Wilson disease 2023-10-19 criteria provided, single submitter clinical testing
Natera, Inc. RCV001069979 SCV001463843 likely pathogenic Wilson disease 2020-09-16 no assertion criteria provided clinical testing

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