ClinVar Genomic variation as it relates to human health

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.

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.

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.

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

Criteria applied: PM3_VSTR,PS3_MOD,PP4

Observed in the homozygous state or with a second variant in patients with prolonged neuromuscular block following anesthesia and/or butyrylcholinesterase deficiency tested at GeneDx and in published literature (PMID: 33774263, 2915989, 11928765, 12881446, 27031121, 25264279); Published functional studies demonstrate a severe reduction in affinity for butyrylthiocholine and succinyldithiocholine (PMID: 9047329, 23123771); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported using alternate nomenclature of D70G, and is also known as the Atypical variant or the A allele; 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, 11749053, 30804560, 1306123, 34204301, 12881446, 27031121, 30487145, 36199823, 35026467, 9047329, 33774263, 37520883)

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.

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.

The p.Asp98Gly variant in BCHE (also described as p.Asp70Gly or the A allele in the literature) has been reported in the homozygous or compound heterozygous state in >40 individuals with pseudocholinesterase deficiency and segregated with disease in 9 affected relatives from 4 families (McGuire 1989 PMID: 2915989, Yen 2003 PMID: 12881446, Levano 2005 PMID: 15731589, Zelinski 2007 PMID: 17166756, Parnas 2011 PMID: 21228368, Garcia 2011 PMID: 21637541, Zavorotnyy 2011 PMID: 22053728, Delacour 2014 PMID: 25054547). The majority of these individuals carried another variant (p.Ala567Thr, also known as the K allele) on the same copy of the BCHE gene (in cis). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 13215) and has been identified in 1.2% (1897/152168) of total chromosomes, including 18 homozygous individuals, by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). This frequency is consistent with the frequency of pseudocholinesterase deficiency in the general population and the conditions under which clinical symptoms manifest. In vitro functional studies provide evidence that the p.Asp98Gly variant impacts BCHE enzyme activity (Masson 1997 PMID: 9047329, Lockridge 2016 PMID: 27551784). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp98Gly variant is likely pathogenic for autosomal recessive pseudocholinesterase deficiency. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PP1_Moderate.

BCHE: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4

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.

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.

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.

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.