ClinVar Genomic variation as it relates to human health

A variant of uncertain significance has been identified in the ATP8B1 gene. The K203E variant has previously been identified as heterozygous in a single individual with intrahepatic cholestasis of pregnancy (Painter et al., 2005). The K203E variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K203E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Variant summary: ATP8B1 c.607A>G (p.Lys203Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00089 in 253652 control chromosomes in the gnomAD database, including 1 homozygotes (gnomAD, Painter_2005, van der Woerd_2013). This frequency is not significantly higher than expected for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis (0.00089 vs 0.0022), allowing no conclusion about variant significance. c.607A>G has been reported in the literature in individuals affected with Cholestasis and Pancreatic disease (e.g. Painter_2005, van der Woerd_2013, Dixon_2017, Vitale_2018), including one homozygote (Gouveia_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.

BS1

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 individual with intrahepatic cholestasis of pregnancy (Painter 2005).

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).