ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Variant summary: ATP7B c.3045G>A alters a conserved nucleotide resulting in a synonymous change. At least one computational tool predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.025 in 218250 control chromosomes in the gnomAD database, including 112 homozygotes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), strongly suggesting that the variant is benign. c.3045G>A has been reported in the literature in individuals affected with Wilson Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease.Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with consensus of benign (benign/likely benign n=7, likely pathogenic n=1, VUS n=1) . Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The c.3045G>A variant is predicted to encode a synonymous change (p.Leu1015Leu) in exon 13 of ATP7B. The prevalence of this variant in the gnomAD database (MAF=0.02544, 126 homozygotes) suggests that it is far too common to cause disease in homozygous state. However, we identified this variant in compound-heterozygous state with a well-established pathogenic truncating variant (p.Arg1319*). Research RNA-seq of proband liver tissue established that the p.Leu1015Leu variant causes exon 13 skipping in approximately 1/3 of transcripts. We propose that this variant is a hypomorphic allele that only causes disease when compound-heterozygous with a loss-of-function variant. We therefore interpret the p.Leu1015Leu variant as likely pathogenic.