ClinVar Genomic variation as it relates to human health

Variant summary: ATP7B c.1145_1151delCCCAACT (p.Ser382TrpfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1531C>T (p.Gln511X), c.1716delG (p.Met573X), and c.1745_1746delTA (p.Ile582fsX25)). The variant allele was found at a frequency of 1.4e-05 in 277184 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (1.4e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.1145_1151delCCCAACT, has been reported in the literature in multiple individuals affected with Wilson Disease (Curtis_1999, Coffey_2013). 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as "pathogenic/likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Identified in patients with Wilson disease (Curtis et al., 1999); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10502777)

This sequence change creates a premature translational stop signal (p.Ser382Trpfs*24) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 10502777). This variant is also known as 1143del7. ClinVar contains an entry for this variant (Variation ID: 523941). For these reasons, this variant has been classified as Pathogenic.

PM2, PVS1

The p.Ser382TrpfsX24 variant in ATP7B has been previously reported in 3 alleles from a cohort of British patients with Wilson disease (Curtis 1999). It has also been reported in six compound heterozyous patients with Wilson disease (Coffey 2013). This variant has been identified 1/24204 African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 382 and leads to a premature termination codon 24 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP4.