rs745364489

chr3-165829794-G-Achr3-165829794-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000055.4(BCHE):c.1240C>T(p.Arg414Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.13

Genes affected

BCHE (HGNC:983): (butyrylcholinesterase) This gene encodes a cholinesterase enzyme and member of the type-B carboxylesterase/lipase family of proteins. The encoded enzyme exhibits broad substrate specificity and is involved in the detoxification of poisons including organophosphate nerve agents and pesticides, and the metabolism of drugs including cocaine, heroin and aspirin. Humans homozygous for certain mutations in this gene exhibit prolonged apnea after administration of the muscle relaxant succinylcholine. [provided by RefSeq, Jul 2016]

LINC01322 (HGNC:50528): (long intergenic non-protein coding RNA 1322)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 3-165829794-G-A is Pathogenic according to our data. Variant chr3-165829794-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCHE	NM_000055.4	c.1240C>T	p.Arg414Cys	missense_variant	2/4	ENST00000264381.8
BCHE	NR_137636.2	n.1358C>T		non_coding_transcript_exon_variant	2/5
BCHE	NR_137635.2	n.110+7520C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCHE	ENST00000264381.8	c.1240C>T	p.Arg414Cys	missense_variant	2/4	1	NM_000055.4	P1
LINC01322	ENST00000651449.1	n.1008-16098G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250530 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151922 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74196

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyrylcholinesterase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2023	Variant summary: BCHE c.1240C>T (p.Arg414Cys) results in a non-conservative amino acid change located in the Carboxylesterase, type B (IPR002018) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250530 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (4e-05 vs 0.016), allowing no conclusion about variant significance. c.1240C>T has been reported in the literature in individuals affected with Deficiency Of Butyrylcholine Esterase (Whittington_2012, Yen_2003, On-Kei_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrates reduced enzyme activity in a homozygous patient (Whittington_2012) and in recombinant cells (Brazzolotto_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33024248, 15563885, 22378569, 12881446). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2017	- -

BCHE-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2022

The BCHE c.1240C>T variant is predicted to result in the amino acid substitution p.Arg414Cys. This variant (referred to as p.Arg386Cys in the literature) was previously reported, also in the homozygous state, in a patient who presented with post-succinylcholine paralysis and severely reduced butyrylcholinesterase enzyme activity (Whittington et al. 2012. PubMed ID: 22378569). In vitro analysis of recombinant variant protein suggested that the p.Arg414Cys change results in retention of the variant protein in the endoplasmic reticulum (Brazzolotto et al. 2020. PubMed ID: 33024248). Additionally, this variant was also identified in the heterozygous state in an individual who presented with prolonged post-succinylcholine apnea (Yen et al. 2003. PubMed ID: 12881446). At PreventionGenetics, we previously identified this variant in the apparently homozygous state in an individual with suspected BCHE deficiency after an adverse reaction post-surgery (internal data). Taken together, we classify the c.1240C>T variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.84		Loss of disorder (P = 0.0083);
MVP		1.0
MPC		0.11
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745364489; hg19: chr3-165547582; COSMIC: COSV52259719;