ClinVar Miner

Submissions for variant NM_000055.2(BCHE):c.1253G>T (p.Gly418Val) (rs28933390)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000360109 SCV000442037 uncertain significance Deficiency of butyrylcholine esterase 2017-09-14 criteria provided, single submitter clinical testing The BCHE c.1253G>T (p.Gly418Val) missense variant, also known as p.Gly390Val or F-2, is one of the two substitutions resulting in the known BCHE fluoride-resistant phenotype with sensitivity to succinyldicholine. When Nogueira et al. (1992) analyzed DNA from 25 patients who had the fluoride-resistant phenotype, the p.Gly418Val variant was identified in three patients in a compound heterozygous state and seven patients in a heterozygous state from four different families. Yen et al. (2003) investigated the BCHE gene in 65 patients who had prolonged post-succinylcholine apnea and the p.Gly418Val variant was identified in two individuals where zygosity was not reported. Jasiecki et al. (2016) further identified the p.Gly418Val variant in a heterozygous state in thirteen individuals with aberrant fluoride levels, however the BChE activity levels were in the normal range in these individuals. Control data are unavailable for this variant, which is reported at a frequency of 0.01869 in the Toscani in Italy population of the 1000 Genomes project. Based on the available evidence, the p.Gly418Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000360109 SCV000485282 pathogenic Deficiency of butyrylcholine esterase 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000360109 SCV001653083 likely pathogenic Deficiency of butyrylcholine esterase 2020-07-03 criteria provided, single submitter clinical testing The p.Gly418Val variant in BCHE (also reported as p.Gly390Val or the Fluoride-2 allele) has been reported in 4 individuals with succinylcholine-induced apnea and at least 7 additional individuals with pseudocholinesterase deficiency, all in the homozygous or compound heterozygous state. It has also been identified in at least 19 heterozygous carriers who often displayed mild pseudocholinesterase deficiency (Noguiera 1992 PMID: 1415224, Yen 2003 PMID 12881446, Lando 2003 PMID: 12724618, Mikami 2008 PMID: 18300943, Parnas 2011 PMID 21228368, Jasiecki 2016 PMID:27109752). This variant has also been reported in ClinVar (Variation ID: 13219) and has also been identified in 0.5% (647/128524) of total chromosomes, including 3 homozygous individuals, by gnomAD (http://gnomad.broadinstitute.org). This frequency is consistent with the frequency of pseudocholinesterase deficiency in the general population. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In vitro functional studies provide evidence that the p.Gly418Val variant impacts BCHE enzyme activity (Masson 1997 PMID: 9047329). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly418Val variant is likely pathogenic for autosomal recessive pseudocholinesterase deficiency. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, BP4.
OMIM RCV000014116 SCV000034364 pathogenic BCHE, fluoride 2 2018-04-24 no assertion criteria provided literature only

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