rs28933390
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_000055.4(BCHE):c.1253G>T(p.Gly418Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,613,898 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000055.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCHE | NM_000055.4 | c.1253G>T | p.Gly418Val | missense_variant | 2/4 | ENST00000264381.8 | |
BCHE | NR_137636.2 | n.1371G>T | non_coding_transcript_exon_variant | 2/5 | |||
BCHE | NR_137635.2 | n.110+7533G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCHE | ENST00000264381.8 | c.1253G>T | p.Gly418Val | missense_variant | 2/4 | 1 | NM_000055.4 | P1 | |
LINC01322 | ENST00000651449.1 | n.1008-16111C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00312 AC: 475AN: 152090Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00313 AC: 784AN: 250680Hom.: 3 AF XY: 0.00322 AC XY: 436AN XY: 135470
GnomAD4 exome AF: 0.00413 AC: 6034AN: 1461690Hom.: 17 Cov.: 31 AF XY: 0.00403 AC XY: 2929AN XY: 727136
GnomAD4 genome ? AF: 0.00312 AC: 475AN: 152208Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239AN XY: 74420
ClinVar
Submissions by phenotype
Deficiency of butyrylcholinesterase Pathogenic:3Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 03, 2020 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2023 | Variant summary: BCHE c.1253G>T (p.Gly418Val) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 250680 control chromosomes in the gnomAD V2 database, including 3 homozygotes. This frequency is lower than the estimated maximum expected for a pathogenic variant in BCHE causing Deficiency of Butyrylcholine Esterase (0.016), allowing no conclusion about variant significance. The variant c.1253G>T has been reported in the literature in compound heterozygous state either in individuals manifesting increased sensitivity to muscle relaxants, such as succinylcholine (e.g. Greenberg_1995, Yen_2003) or was reported as a biochemical phenotype, based on altered cholinesterase activities by various in vitro enzyme assays (e.g. Nogueira_1992, Lando_2003, Jasiecki_2016). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated an increased Km value for succinyldithiocholine for the variant protein, causing a reduction in substrate affinity, therefore the authors concluded that the rate of hydrolysis of succinyldicholine should be slower when its concentration is in the pharmacologic range (Masson_1993). The following publications have been ascertained in the context of this evaluation (PMID: 7618741, 31980526, 27109752, 12724618, 8314794, 1415224, 12881446). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with butyrylcholinesterase deficiency (MIM#617936). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (856 heterozygotes, 3 homozygotes). (SP) 0309 - Three alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele: 1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated carboxylesterase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is known as p.(Gly390Val) or F2 allele in the literature, and has been reported in multiple heterozygous, homozygous or compound heterozygous individuals with prolonged apnoea (PMID: 1415224, 12881446, 12724618, 18300943, 27109752). It has also been reported as VUS, likely pathogenic and pathogenic in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrate the variant bounds substrates and ligands less tightly than the WT, which may result in moderate succinyldicholine hypersensitivity (PMID: 8314794). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 20, 2021 | NM_000055.2(BCHE):c.1253G>T(G418V) is a missense variant classified as a variant of uncertain significance in the context of pseudocholinesterase deficiency. G418V has been observed in cases with relevant disease (PMID: 12724618, 12881446, 1415224). Functional assessments of this variant are available in the literature (PMID: 8314794). G418V has been observed in population frequency databases (gnomAD: NFE 0.51%). In summary, there is insufficient evidence to classify NM_000055.2(BCHE):c.1253G>T(G418V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 14, 2017 | 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. - |
BCHE-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 08, 2023 | The BCHE c.1253G>T variant is predicted to result in the amino acid substitution p.Gly418Val. This variant (also known as the fluoride-2, flu-2, or F-2 variant) has been described in patients with reduced butyrylcholinesterase activity and may be associated with an increased risk for post-anesthesia apnea following exposure to neuromuscular blocking agents such as succinylcholine (Nogueira et al. 1992. PubMed ID: 1415224, reported as p.Gly390Val; Yen et al. 2003. PubMed ID: 12881446; Masson et al. 1993. PubMed ID: 8314794; Jasiecki et al. 2016. PubMed ID: 27109752; Lando et al. 2003. PubMed ID: 12724618; Mikami et al. 2008. PubMed ID: 18300943; Greenberg et al. 1995. PubMed ID: 7618741). Although rare in the general population, the F-2 variant has been reported in smaller subpopulations at allele frequencies as high as ~0.5%. This variant is also referred to as Gly390Val in the literature. We classify this variant as likely pathogenic. - |
BCHE, fluoride 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 24, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at