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

gnomAD frequency: 0.00057  dbSNP: rs28933389

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779401	SCV000916009	likely pathogenic	Deficiency of butyrylcholinesterase	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 butyrylcholinesterase	2024-01-11	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). The following publications have been ascertained in the context of this evaluation (PMID: 2013061, 2253336, 12724618, 1415224, 12881446, 33010031). ClinVar contains an entry for this variant (Variation ID: 13218). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001753416	SCV002005064	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing	Classified by the PharmGKB project as a polymorphism associated with prolonged apnea, with alternate names listed as F-Variant, BCHE*243M, and Thr243Met (Alvarellos et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 2253336, 1415224, 11928765, 13711731, 15563885, 12724618, 2013061, 26398623, 12881446, 31589614)
OMIM	RCV000014112	SCV000034360	pathogenic	BCHE, flouride 1	1992-10-01	no assertion criteria provided	literature only