chr3-165829781-C-A

Variant names:

• chr3-165829781-C-A
• rs28933390
• NM_000055.4:c.1253G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (17 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 1.39

Genes affected

BCHE (HGNC:983): (butyrylcholinesterase) This gene encodes a cholinesterase enzyme and member of the type-B carboxylesterase/lipase family of proteins. The encoded enzyme exhibits broad substrate specificity and is involved in the detoxification of poisons including organophosphate nerve agents and pesticides, and the metabolism of drugs including cocaine, heroin and aspirin. Humans homozygous for certain mutations in this gene exhibit prolonged apnea after administration of the muscle relaxant succinylcholine. [provided by RefSeq, Jul 2016]

LINC01322 (HGNC:50528): (long intergenic non-protein coding RNA 1322)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP5: Variant 3-165829781-C-A is Pathogenic according to our data. Variant chr3-165829781-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13219.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01191321). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCHE	NM_000055.4	c.1253G>T	p.Gly418Val	missense_variant	Exon 2 of 4	ENST00000264381.8	NP_000046.1
BCHE	NR_137636.2	n.1371G>T		non_coding_transcript_exon_variant	Exon 2 of 5
BCHE	NR_137635.2	n.110+7533G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8	c.1253G>T	p.Gly418Val	missense_variant	Exon 2 of 4	1	NM_000055.4	ENSP00000264381.3

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00313 AC: 784 AN: 250680 Hom.: 3 AF XY: 0.00322 AC XY: 436 AN XY: 135470

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00520

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00413 AC: 6034 AN: 1461690 Hom.: 17 Cov.: 31 AF XY: 0.00403 AC XY: 2929 AN XY: 727136

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.00487

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74420

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00535 Hom.: 5

Bravo AF: 0.00332

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00301 AC: 366

EpiCase AF: 0.00720

EpiControl AF: 0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of butyrylcholinesterase Pathogenic:4 Uncertain:1

Nov 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 17, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253G>T (p.Gly418Val) variant affects a weakly conserved amino acid and is predicted by multiple in silico tools to have a benign effect on protein function. This variant has been previously reported as a compound heterozygous and homozygous change in individuals with butyrylcholinesterase deficiency (PMID: 1415224, 12724618, 12881446, 27109752, 7618741). Functional studies indicate this variant may lead to reduced butyrylcholinesterase enzyme activity (PMID: 8314794, 12724618). The c.1253G>T (p.Gly418Val) variant is present in the latest gnomAD population database at an allele frequency of 0.4 % (6509/1613898), including 18 homozygous individuals. Based on the available evidence, c.1253G>T (p.Gly418Val) is classified as Likely Pathogenic. -

Jul 03, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 20, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 <0.01 for a recessive condition (v4: 6473 heterozygotes, 18 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 -

BCHE-related disorder Pathogenic:1

Dec 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 24, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.23	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.077
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.088	B
Vest4		0.27
MVP		0.85
MPC		0.032
ClinPred		0.052	T
GERP RS		3.1
Varity_R		0.76
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28933390; hg19: chr3-165547569; COSMIC: COSV52263145;