ClinVar Miner

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

gnomAD frequency: 0.01086  dbSNP: rs1799807
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000277104 SCV000442044 pathogenic Deficiency of butyrylcholinesterase 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 butyrylcholinesterase 2018-10-31 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 Women's Health, 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 2019-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000277104 SCV001370742 pathogenic Deficiency of butyrylcholinesterase 2022-02-20 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). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=7), likely pathogenic (n=2) and risk factor (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001092437 SCV002004685 likely pathogenic not provided 2022-05-12 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; 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, 1306123, 30804560, 34204301, 11749053, 12881446, 27031121, 30487145)
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.
PerkinElmer Genomics RCV000277104 SCV002024584 pathogenic Deficiency of butyrylcholinesterase 2021-05-03 no assertion criteria provided clinical testing

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