ClinVar Genomic variation as it relates to human health

The BCHE c.1072T>A (p.Leu358Ile) missense variant, also known as p.Leu330Ile, has been reported in at least five studies and is found in a total of 15 individuals with butyrylcholinesterase deficiency, including in two in a homozygous state, in two in a compound heterozygous state, and in eleven in a heterozygous state (Iida et al. 1995; Maekawa et al. 1997; Sudo et al. 1997; Asanuma et al. 1999; Liu et al. 2002). Ten of the 11 heterozygous individuals had a moderate reduction of their serum cholinesterase activity, in contrast to the two homozygous and the two compound heterozygous individuals, who all had a severe reduction of their serum cholinesterase activity. Control data are unavailable for this variant, which is reported at a frequency of 0.00106 in the East Asian population of the Genome Aggregation Database. Expression in HEK293 cells revealed that p.Leu358Ile variant had 20% residual serum cholinesterase activity compared to wild type (Liu et al. 2002). Based on the collective evidence, the p.Leu358Ile variant is classified as pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: BCHE c.1072T>A (p.Leu358Ile) results in a conservative amino acid change located in the Carboxylesterase, type B of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 249532 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (8.8e-05 vs 0.016), allowing no conclusion about variant significance. c.1072T>A has been reported in the literature in individuals affected with Deficiency Of Butyrylcholine Esterase (e.g. Iida_1995, Sudo_1997, Liu_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sudo_1997, Liu_2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.