ClinVar Genomic variation as it relates to human health

Most common pathogenic variant identified in individuals with Wilson disease in India (PMID: 31059521, 24094725); Nonsense 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; This variant is associated with the following publications: (PMID: 31589614, 25525159, 30426382, 34643937, 35342245, 9887381, 24094725, 23551039, 23518715, 31059521)

Variant summary: ATP7B c.813C>A (p.Cys271X) 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. The variant allele was found at a frequency of 9.4e-05 in 244686 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (9.4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.813C>A, has been reported in the literature in multiple individuals affected with Wilson Disease (Mukherjee_2014, Coffey_2013, Duc_1998). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The stop gained p.C271Ter in ATP7B (NM_000053.3) has been previously reported in multiple patients affected with Wilson disease (Aggarwal A et al, 2013; Mukherjee S et al, 2014). It has been reported in the ClinVar database as Pathogenic. The p.C271Ter variant is observed in 2/978 (0.2045%) alleles from individuals of South Asian background in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Cys271*) 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 (rs572147914, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 21034864, 30426382, 31059521). ClinVar contains an entry for this variant (Variation ID: 188930). For these reasons, this variant has been classified as Pathogenic.

The p.Cys271X variant in ATP7B has been previously reported in many homozygous and compound heterozygous individuals with Wilson disease, and segregated with disease in at least two affected relatives (Aggarwal 2013, Coffey 2013, Duc 1998, Gupta 2005, Khan 2018, Lee 2011, Mukerjee 2014, Santhosh 2006). The majority of these individuals were from the Indian subcontinent. This variant has also been identified in 0.07% (23/30584) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 271, which is 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_VeryStrong, PP1_Moderate, PP4.

PP1, PM2, PVS1

This variant changes 1 nucleotide in exon 2 of the ATP7B gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous and homozygous states in many individuals affected with Wilson disease and is one of the most common mutations in India associated with Wilson disease (PMID: 9887381, 16133174, 17264425, 21034864, 21645214, 23518715, 23551039, 24094725, 30426382, 31059521). This variant has been identified in 24/247982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The ATP7B c.813C>A variant is predicted to result in premature protein termination (p.Cys271*). This variant has been detected in the homozygous and compound heterozygous state in a large number of individuals with Wilson disease, particularly of East Indian descent (Duc et al. 1998. PubMed ID: 9887381; Mukherjee et al. 2014. PubMed ID: 24094725). It is listed as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/188930/). This variant is reported in 0.075% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic.