ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2755C>T (p.Arg919Trp) (rs121907993)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000388607 SCV000384667 uncertain significance Wilson disease 2017-04-28 criteria provided, single submitter clinical testing The ATP7B c.2755C>T (p.Arg919Trp) missense variant has been reported in at least five studies in which it was found in a compound heterozygous state in two siblings with Wilson disease, in a heterozygous state in one affected individual, and in at least three individuals of unknown zygosity (Loudianos et al. 1998; Lepori et al. 2007; Simsek Papur et al. 2013; Merle et al. 2013; Louidanos et al. 2013). The variant was also found in a heterozygous state in an unaffected parent. The p.Arg919Trp variant was absent from 104 control alleles as part of one of the studies but was reported in a heterozygous state in one of 1008 newborns (Coffey et al. 2013). The variant is reported at a frequency of 0.00031 in the African population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg919Trp variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000388607 SCV000694429 likely pathogenic Wilson disease 2019-06-13 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2755C>T (p.Arg919Trp) 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 6.4e-05 in 251064 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.2755C>T has been reported in the literature in individuals affected with Wilson Disease (Loudianos_2013, Maleki_2013, Wei_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000388607 SCV000800765 likely pathogenic Wilson disease 2017-05-22 criteria provided, single submitter clinical testing
Invitae RCV000388607 SCV000960138 likely pathogenic Wilson disease 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 919 of the ATP7B protein (p.Arg919Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121907993, ExAC 0.03%). This variant has been observed to segregate with Wilson disease in a family and has been observed to be homozygous in an unrelated individual with this condition (PMID: 23219664, 25089800). ClinVar contains an entry for this variant (Variation ID: 312386). 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"). Variants that disrupt the p.Arg919 amino acid residue in ATP7B have been observed in affected individuals (PMID: 23219664, 25089800, 21796144, 26032686, 17680703, 12376745, 11405812). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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