ClinVar Miner

Submissions for variant NM_000055.2(BCHE):c.812C>T (p.Thr271Met) (rs28933389)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779401 SCV000916009 likely pathogenic Deficiency of butyrylcholine esterase 2019-01-10 criteria provided, single submitter clinical testing The BCHE c.812C>T (p.Thr271Met) missense variant, also known as p.Thr243Met, is one of two known fluoride-resistant variants that affect sensitivity to succinylcholine. This variant has been reported in at least three studies and was found in a total of five probands, including in four in a compound heterozygous state, two of whom were related, and in one in a heterozygous state (Nogueira et al. 1992; Lando et al. 2003; Yen et al. 2003). Two additional related individuals with this variant were also reported by La Du et al. (1990). Control data are not available for this variant, which is reported at a frequency of 0.00091 in the African American population of the Exome Sequencing Project. The p.Thr271Met variant affects a glycosylation site on the BCHE protein, reducing the number of carbohydrate chains attached to the mature protein (Nogueira et al. 1992). Based on the evidence, the p.Thr271Met variant is classified as likely pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779401 SCV001338374 likely pathogenic Deficiency of butyrylcholine esterase 2020-02-21 criteria provided, single submitter clinical testing Variant summary: BCHE c.812C>T (p.Thr271Met, legacy name Thr243Met or the flu-1 allele) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (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 0.00044 in 250754 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency of butyrylcholine esterase (0.00044 vs 0.016), allowing no conclusion about variant significance. c.812C>T has been reported in the literature among compound heterozygous individuals affected with a deficiency of butyrylcholine esterase manifesting as the fluoride-resistant phenotype (example, Nogueira_1992, Yen_2003 and LaDu_1990). It has subsequently been cited in the literature (example, LaDu_1991 and Lando_2003). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although a decrease in the number of carbohydrate chains per subunit, from nine to eight, has been attributed to the loss of Threonine residue in this variant (Nogueira_1992). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000014112 SCV000034360 pathogenic BCHE, flouride 1 1992-10-01 no assertion criteria provided literature only

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