ClinVar Miner

Submissions for variant NM_000055.2(BCHE):c.293A>G (p.Asp98Gly) (rs1799807)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000277104 SCV000442044 pathogenic Deficiency of butyrylcholine esterase 2017-10-18 criteria provided, single submitter clinical testing The BCHE c.293A>G (p.Asp98Gly) missense variant is well-described in the literature, more commonly referred to as p.Asp70Gly, BCHE*A, BCHE*70G or CHE*70G. Homozygosity for this variant causes the atypical BCHE phenotype, first described by Kalow and Genest (1957). McGuire et al. (1989) 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 atypical subjects tested. Yen et al. (2003) genotyped 52 individuals in Australia with post-succinylcholine (SC) apnea attributable to BCHE variants. The p.Asp98Gly variant (A allele) was found in 47/52 individuals 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 individuals. Twenty-three individuals were homozygous for both the A allele and the K allele (AAKK), the most common genotype. In addition seven individuals 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. This study indicated that compound genotypes are most often associated with post-succinylcholine (SC) apnea. In a review by Lockridge (2015), 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 agrees with the highest reported allele frequency of 0.03738 in the Toscani in Italy population of the 1000 Genomes Project, confirming that this is a common variant. Based on the collective evidence, the p.Asp98Gly variant is classified as pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics,Fulgent Genetics RCV000277104 SCV000894304 pathogenic Deficiency of butyrylcholine esterase 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000277104 SCV000967600 likely pathogenic Deficiency of butyrylcholine esterase 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,; 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 Women's Health, Inc. RCV000277104 SCV001194045 likely pathogenic Deficiency of butyrylcholine esterase 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 butyrylcholine esterase 2018-10-12 criteria provided, single submitter clinical testing A homozygous missense variant, NM_000055.2(BCHE):c.293A>G, has been identified in exon 2 of 4 of the BCHE gene. The variant is predicted to result in a moderate amino acid change from an aspartic acid to glycine at position 98 of the protein, NP_000046.1(BCHE):p.(Asp98Gly). The aspartic acid residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 1.2% (3235 heterozygotes, 36 homozygotes). The variant has previously been described as pathogenic in multiple patients with atypical butyrylcholinesterase deficiency (ClinVar). It has also been shown to segregate in a large family (McGuire, M., et al. (1989)). Additionally, it was reported that patient serum exhibited about 50% butyrylcholinesterase activity and a 100-fold reduction of substrate binding activity (Lockridge, O. (2015), McGuire, M., et al. (1989)). A different variant in the same codon resulting in a change to a histidine, p.(Asp98His) has also been shown to cause butyrylcholinesterase deficiency (Boeck, et al. (2002)). Analysis of parental samples indicated that both parents are carriers of the variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092437 SCV001248950 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000277104 SCV001370742 pathogenic Deficiency of butyrylcholine esterase 2020-05-29 criteria provided, single submitter clinical testing Variant summary: BCHE c.293A>G (p.Asp98Gly; legacy names D70G and atypical variant A) 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 was 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). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=7) and as risk factor (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000014102 SCV000034350 pathogenic Postanesthetic apnea 1991-02-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000277104 SCV000607344 not provided Deficiency of butyrylcholine esterase no assertion provided phenotyping only 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 butyrylcholine esterase 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.

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