Submissions for variant NM_000055.2(BCHE):c.293A>G (p.Asp98Gly)

gnomAD frequency: 0.01259  dbSNP: rs1799807

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001092437	SCV000442044	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	The BCHE c.293A>G (p.Asp98Gly) missense variant results in the substitution of aspartic acid at amino acid position 98 with glycine. This variant is well-described in the literature, more commonly referred to as p.Asp70Gly, BCHE*A, BCHE*70G or BCHE*70G. Homozygosity for this variant causes the atypical butyrylcholinesterase (BCHE) deficiency phenotype, first described by Kalow in 1957 (PMID: 13437188). McGuire et al. (1989) (PMID: 2915989) studied 26 individuals with the atypical phenotype, including 15 individuals from a large three-generation family. They found complete concordance between the p.Asp98Gly variant and serum cholinesterase phenotypes for all individuals tested. Yen et al. (2003) (PMID: 12881446) genotyped 52 patients in Australia with post-succinylcholine apnea attributable to BCHE variants. The p.Asp98Gly variant (A allele) was found in 47/52 patients with an allele frequency of 0.72. Co-inheritance of the A allele and another well-described variant, p.Ala567Thr (the K allele) occurred in 88% of patients. Twenty-three patients were homozygous for both the A allele and the K allele (AAKK), the most common genotype. In addition seven patients were compound heterozygotes for the A allele and the K allele (AK), four were homozygous for the A allele and heterozygous for the K allele (AAK), four were heterozygous for the A allele and homozygous for the K allele (AKK) and nine had compound genotypes with other variants in the BCHE gene. Their study indicated that compound genotypes are most often associated with post-succinylcholine apnea. In a review (PMID: 25448037), the p.Asp98Gly variant is reported to have 50% enzyme activity, to reduce the binding affinity for succinylcholine 100-fold and to have a carrier frequency of 1/25. This is consistent with the highest reported allele frequency of 0.01766 (including 30 homozygotes) in the European (non-Finnish) population of the Genome Aggregation Database, confirming that this is a common variant. Based on the available evidence, the p.Asp98Gly variant is classified as pathogenic for butyrylcholinesterase deficiency.
Fulgent Genetics, Fulgent Genetics	RCV000277104	SCV000894304	pathogenic	Deficiency of butyrylcholinesterase	2022-05-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000277104	SCV000967600	likely pathogenic	Deficiency of butyrylcholinesterase	2018-06-15	criteria provided, single submitter	clinical testing	The p.Asp98Gly variant in BCHE (also reported as p.Asp70Gly or the A allele) has been reported in the homozygous or compound heterozygous state in >40 individua ls with pseudocholinesterase deficiency and segregated with disease in 9 affecte d members of 4 families (McGuire 1989, Yen 2003, Levano 2005, Zelinski 2007, Par nas 2011, Garcia 2011, Zavorotnyy 2011, Delacour 2014). The majority of these in dividuals carried another variant (p.Ala567Thr, also known as the K allele) on t he same copy of the BCHE gene (in cis). In vitro functional studies provide evid ence that the p.Asp98Gly variant impacts BCHE enzyme activity (Masson 1997, Lock ridge 2016). However, these types of assays may not accurately represent biologi cal function. This variant has also been identified in 1.2% (3307/276762) of tot al chromosomes, including 36 homozygous individuals, by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1799807). This freque ncy is consistent with the frequency of pseudocholinesterase deficiency in the g eneral population. Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Asp98Gly variant is likely pathogenic. ACMG/AMP Criteria applied: PM 3; PS3_Moderate; PP1_Moderate.
Myriad Genetics, Inc.	RCV000277104	SCV001194045	likely pathogenic	Deficiency of butyrylcholinesterase	2019-12-09	criteria provided, single submitter	clinical testing	NM_000055.2(BCHE):c.293A>G(D98G, aka D70G) is classified as likely pathogenic in the context of pseudocholinesterase deficiency. Sources cited for classification include the following: PMID 9047329, 10446378, 21228368 and 17166756. Classification of NM_000055.2(BCHE):c.293A>G(D98G, aka D70G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000277104	SCV001245019	pathogenic	Deficiency of butyrylcholinesterase	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 aspartic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 3313 heterozygotes, 36 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated carboxylesterase domain (DECIPHER, NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Asp70Gly) or A allele in the literature, it has been reported in at least ten homozygous or compound heterozygous patients who had prolonged duration of action involving succinylcholine or mivacurium during anaesthesia and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 12881446, 27031121). (SP) 1207 - Parental origin of the variant is unresolved [DETAILS (LABID/by trio analysis)]. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV001092437	SCV001248950	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BCHE: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000277104	SCV001370742	pathogenic	Deficiency of butyrylcholinesterase	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: BCHE c.293A>G (p.Asp98Gly) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 250996 control chromosomes, predominantly at a frequency of 0.018 within the Non-Finnish European subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase phenotype. c.293A>G has been reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Deficiency Of Butyrylcholine Esterase resulting in sensitivity to muscle relaxants such as succinylcholine and mivacurium (e.g. Delacour_2014, Garcia_2011, Lockridge_2015, McGuire_1989, Yen_2003). Majority of individuals were determined to have another variant in cis, known as the K-allele (p.Ala539Thr). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant negatively affects enzyme activity and concentration, causing a reduction in substrate affinity and an abolition of substrate activation (e.g. Delacour_2014, Lockridge_2016, Masson_1999). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic /likely pathogenic (n=10) and risk factor (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001092437	SCV002004685	likely pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Observed in the homozygous state or with a second variant in patients with prolonged neuromuscular block following anesthesia and/or butyrylcholinesterase deficiency in published literature (McGuire et al., 1989; Boeck et al., 2002; Yen et al., 2003; Delacour et al., 2014; Wichmann et al., 2016; Millet et al., 2021); Published functional studies demonstrate a severe reduction in affinity for butyrylthiocholine and succinyldithiocholine (Masson et al., 1997; David et al., 2013); Reported using alternate nomenclature of D70G, and is also known as the Atypical variant or the A allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 2013061, 33010031, 23123771, 25054547, 25264279, 11928765, 27109752, 19272534, 27551784, 26444431, 21637541, 25448037, 13437188, 10446378, 21228368, 25741868, 3542989, 13479831, 14404182, 31071335, 26439437, 31942019, 34313030, 17166756, 2915989, 9047329, 33774263, 11749053, 30804560, 1306123, 34204301, 12881446, 27031121, 30487145, 36199823, 35026467)
Revvity Omics, Revvity	RCV000277104	SCV002024584	pathogenic	Deficiency of butyrylcholinesterase	2023-03-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000277104	SCV002578949	pathogenic	Deficiency of butyrylcholinesterase	2022-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001092437	SCV003799857	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	The BCHE c.293A>G; p.Asp98Gly variant (rs1799807), also published as D70G, the atypical variant, or the A allele, is reported in the literature in many individuals with butyrylcholinesterase deficiency and individuals homozygous for this variant have a prolonged apnea after a standard dose of succinylcholine or mivacurium (e.g., see Delacour 2014, Lockridge 2016, McGuire 1989). This variant is found in the general population with an overall allele frequency of 1.2% (3,385/282,392 alleles, including 36 homozygotes) in the Genome Aggregation Database (v2.1.1). Functional studies show the variant causes reduced enzyme activity and a reduction in substrate affinity/activation (Delacour 2014, Lockridge 2016, Masson 1999). Additionally, the variant is classified as likely pathogenic or pathogenic by several sources in the ClinVar database (Variation ID: 13215). Based on available information, this variant is classified as pathogenic. References: Delacour H et al. Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged apnea with suxamethonium. PLoS One. 2014 Jul 23;9(7):e101552. PMID: 25054547. Garcia DF et al. Biochemical and genetic analysis of butyrylcholinesterase (BChE) in a family, due to prolonged neuromuscular blockade after the use of succinylcholine. Genet Mol Biol. 2011 Jan;34(1):40-4. PMID: 21637541. Lockridge O et al. Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors. Chem Res Toxicol. 2016 Sep 19;29(9):1381-92. PMID: 27551784. Masson P et al. Interaction between the peripheral site residues of human butyrylcholinesterase, D70 and Y332, in binding and hydrolysis of substrates. Biochim Biophys Acta. 1999 Aug 17;1433(1-2):281-93. PMID: 10446378. McGuire MC et al. Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase. Proc Natl Acad Sci U S A. 1989 Feb;86(3):953-7. PMID: 2915989.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000277104	SCV004046421	pathogenic	Deficiency of butyrylcholinesterase		criteria provided, single submitter	clinical testing	This variant (also known as p.Asp70Gly or the A allele) has been previously reported as a heterozygous and homozygous change in individuals with Butyrylcholinesterase deficiency (PMID: 12881446, 26439437, 30600548, 25054547, 26439437, 30487145, 30804560, 8390770). A meta-analysis showed individuals heterozygous for the A variant had prolonged succinylcholine and mivacurium neuromuscular blockade by 5-10 min and 13-14 min, respectively, in comparison to homozygous individuals who had prolonged neuromuscular blockade for several hours (PMID: 30600548). Functional studies suggest the p.Asp98Gly variant leads to reduced enzyme activity and binding affinity for succinylcholine (PMID: 25448037, 2915989). The c.293A>G (p.Asp98Gly) variant is present in the gnomAD population database at a frequency of 1.1% (3385/282392) in the heterozygous state and a frequency of 0.012% (36/282392) in the homozygous state. The c.293A>G (p.Asp98Gly) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.293A>G (p.Asp98Gly) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415696	SCV004116955	pathogenic	BCHE-related condition	2024-01-09	criteria provided, single submitter	clinical testing	The BCHE c.293A>G variant is predicted to result in the amino acid substitution p.Asp98Gly. This variant is also referred to as p.Asp70Gly in the literature. This variant (known as the atypical, A, or dibucaine-resistant variant) has been documented to reduce butyrylcholinesterase activity by 70% in homozygotes and in homozygotes has been associated with an increased risk for post-anesthesia apnea when exposed to neuromuscular blocking agents such as dibucaine, succinylcholine, and mivacurium (McGuire et al. 1989. PubMed ID: 2915989; Yen et al. 2003. PubMed ID: 12881446; Levano et al. 2005. PubMed ID: 15731589; Parnas et al. 2011. PubMed ID: 21228368; Garcia et al. 2011. PubMed ID: 21637541; Zavorotnyy and Zwanzger. 2011. PubMed ID: 22053728; Delacour et al. 2014. PubMed ID: 25054547). This variant is relatively common (minor allele frequency of ~2% in the European (non-Finnish) population) and is usually carried on the same allele (i.e., in cis) with c.1699G>A (p.Ala567Thr). We classify this variant as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000277104	SCV004171354	pathogenic	Deficiency of butyrylcholinesterase		criteria provided, single submitter	clinical testing
Invitae	RCV001092437	SCV004398535	benign	not provided	2024-01-08	criteria provided, single submitter	clinical testing
OMIM	RCV000014102	SCV000034350	pathogenic	Postanesthetic apnea	1991-02-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000277104	SCV000607344	not provided	Deficiency of butyrylcholinesterase		no assertion provided	phenotyping only	The variant was identified in multiple GenomeConnect participants. Variant interpreted as Pathogenic and reported on 04-18-2019 by Lab or GTR ID 507240 and reported on 10-24-2014 by Lab or GTR ID 504895. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Reproductive Health Research and Development, BGI Genomics	RCV000277104	SCV001142332	risk factor	Deficiency of butyrylcholinesterase	2020-01-06	no assertion criteria provided	curation	NM_000055.2:c.293A>G in the BCHE gene has an allele frequency of 0.018 in European (non-Finnish) subpopulation in the gnomAD database. Functional studies show that p.Asp98Gly has reduced activity and reduced enzyme concentration and cause BChE deficiency (PMID: 27551784, 2915989, 25448037). However, BChE deficiency is a multifactorial disorder. Affected individuals are asymptomatic unless exposed to neuromuscular blocking agents. Taken together, we interprete this variant as risk factor variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001092437	SCV001552522	pathogenic	not provided		no assertion criteria provided	clinical testing	The BCHE p.D98G variant has been identified in multiple patients with Butyrylcholinesterase (BCHE) deficiency and has been found to cosegregate with the deficiency in 8 affected members from three families (Yen_2003_PMID:12881446; Garcia_2011_PMID:21637541; McGuire_1989_PMID:2915989). The p.D98G variant (also referred to as the A-variant) is often found as a compound homozygous variant (in cis) with the BCHE p.A567T variant (also known as the K-variant) (Yen_2003_PMID:12881446; Garcia_2011_PMID:21637541). The p.D98G variant was identified in dbSNP (ID: rs1799807), LOVD 3.0 and ClinVar (classified as pathogenic by Illumina and Fulgent Genetics and as likely pathogenic by Counsyl and for Laboratory for Molecular Medicine). The variant was identified in control databases in 3385 of 282392 chromosomes (36 homozygous) at a frequency of 0.011987 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 2277 of 128920 chromosomes (freq: 0.01766), Ashkenazi Jewish in 178 of 10358 chromosomes (freq: 0.01718), Other in 120 of 7198 chromosomes (freq: 0.01667), European (Finnish) in 301 of 25078 chromosomes (freq: 0.012), Latino in 324 of 35328 chromosomes (freq: 0.009171), African in 85 of 24962 chromosomes (freq: 0.003405), South Asian in 99 of 30606 chromosomes (freq: 0.003235), and East Asian in 1 of 19942 chromosomes (freq: 0.00005). The p.D98 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein. The p.D98G variant is known to cause prolonged apnea when homozygous patients are given succinylcholine, as this variant reduces the binding affinity of succinylcholinesterase, prevents its hydrolysis and therefore causes prolonged paralysis of the breathing muscles (Lockridge_2015_PMID:25448037). In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic for BCHE deficiency.