ClinVar Miner

Submissions for variant NM_000055.4(BCHE):c.428G>A (p.Gly143Asp)

gnomAD frequency: 0.00035  dbSNP: rs201820739
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000371428 SCV000442043 pathogenic Deficiency of butyrylcholinesterase 2018-01-24 criteria provided, single submitter clinical testing The BCHE c.428G>A (p.Gly143Asp) missense variant has been reported in at least six studies in which it is found in a total of 15 individuals with butyrylcholinesterase deficiency, including in one in a homozygous state, in 11 in a compound heterozygous state, and in three in a heterozygous state (Primo-Parmo et al. 1997; Gatke et al. 2001; Yen et al. 2003; Gatke et al. 2007; Levano et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.001183 in the Ashkenazi Jewish population of the Genome Aggregation Database. Gatke et al. (2001) reported that individuals with the p.Gly143Asp variant require up to eight hours to reach clinically sufficient neuromuscular function post-dosing of mivicurium, with active isomers present for up to 90 minutes as compared to healthy adults in which isomers were present for 1.5 to 2.3 minutes. The variant occurs in a highly conserved region of BCHE. Functional studies demonstrated that the p.Gly143Asp variant resulted in significantly reduced or absent BCHE activity and only 40% of wild type expression levels (Primo-Parmo et al. 1997; Gatke et al. 2001; Yen et al. 2003). Based on the evidence, the p.Gly143Asp variant is classified as pathogenic for butyrylcholinesterase deficiency, though many individuals who carry pathogenic BCHE variants do not develop clinical complications. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000371428 SCV000677962 likely pathogenic Deficiency of butyrylcholinesterase 2016-12-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000371428 SCV001338375 pathogenic Deficiency of butyrylcholinesterase 2020-02-21 criteria provided, single submitter clinical testing Variant summary: BCHE c.428G>A (p.Gly143Asp, legacy names G115D and BCHE*115D) results in a non-conservative amino acid change located in the Carboxylesterase, type B (IPR002018) 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 0.00028 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency of butyrylcholine esterase (0.00028 vs 0.016), allowing no conclusion about variant significance. c.428G>A has been reported in the literature in multiple individuals affected with Deficiency of butyrylcholine esterase resulting in sensitivity to muscle relaxants such as succinylcholine and mivacurium (example, Primo-Parmo_1997, Gatke_2001). It has been subsequently cited by others. These data indicate that the variant is very 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% of normal butyrylcholineesterase activity in a homozygous individual (example, Primo-Parmo_1997). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GenomeConnect, ClinGen RCV000371428 SCV002074685 not provided Deficiency of butyrylcholinesterase no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 07-30-2015 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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