ClinVar

Description

Variant summary: ATP7B c.4135C>T (p.Pro1379Ser) results in a non-conservative amino acid change located in the after the TM8 domain (Tang_2019) of 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 0.0011 in 247012 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0011 vs 0.0054), allowing no conclusion about variant significance. c.4135C>T has been reported in the literature in at-least one individual affected with Wilson Disease (Cox_2005) and as a compound heterozygote in an unaffected newborn with a genotype (H1069Q/P1379S) from a family in which the affected proband was homozygous for the other well reported variant (H1069Q/H1069Q) (Bennett_2013). It was also reported in a study among individuals who had no family history or indications of of WD (Collet_2018). Additionally, it was found in four compound heterozygous children with one known pathogenic variant and remain asymptomatic without abnormal laboratory consequences (Yi_2020). Lastly, this variant has been reported in a recent study describing the global prevalence of Wilson disease as one among five most frequently known disease variants citing Cox_2005 (Gao_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on copper transport, protein stability or copper-responsive trafficking (Braiterman_2011). 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=11) and likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.