ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000277104 SCV000678076 likely pathogenic Deficiency of butyrylcholine esterase 2015-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000277104 SCV000894304 pathogenic Deficiency of butyrylcholine esterase 2018-10-31 criteria provided, single submitter clinical testing
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.
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.
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, 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.
OMIM RCV000014102 SCV000034350 pathogenic Postanesthetic apnea 1991-02-01 no assertion criteria provided literature only

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