Variant summary: BCHE c.1004T>C (p.Leu335Pro, also known as the L307P variant) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain 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 0.00026 in 249654 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (0.00026 vs 0.016), allowing no conclusion about variant significance. c.1004T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyrylcholine Esterase, specifically at a relatively higher frequency in the Vysya Indian community (Manoharan_2006). Numerous homozygous individuals were reported in this community, all of whom had no detectable BChE activity, including 4 individuals from the same family. All measures of BChE activity agreed that there was deficient BChE activity, including Western blotting, labeled BCHE protein, transient expression of the mutant in 293T cell lines and expression in transfected Chinese hamster ovary cells. Molecular dynamics studies showed the negligible activity caused by this mutation is possibly due to its structural instability (David_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000055.4(BCHE):c.1004T>C (p.Leu335Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000055.4(BCHE):c.1004T>C (p.Leu335Pro)
Variation ID: 13228 Accession: VCV000013228.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q26.1 3: 165830030 (GRCh38) [ NCBI UCSC ] 3: 165547818 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Feb 4, 2024 Apr 20, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000055.4:c.1004T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000046.1:p.Leu335Pro missense NR_137636.2:n.1122T>C non-coding transcript variant NC_000003.12:g.165830030A>G NC_000003.11:g.165547818A>G NG_009031.1:g.12436T>C P06276:p.Leu335Pro - Protein change
- L335P
- Other names
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S-variant
- Canonical SPDI
- NC_000003.12:165830029:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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protein loss of function; Variation Ontology [ VariO:0043] PubMed: 16788378
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00180 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00026
Exome Aggregation Consortium (ExAC) 0.00033
1000 Genomes Project 30x 0.00141
1000 Genomes Project 0.00180
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BCHE | - | - |
GRCh38 GRCh37 |
180 | 202 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2023 | RCV000014132.27 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000678180.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Aug 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyrylcholinesterase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821296.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: BCHE c.1004T>C (p.Leu335Pro, also known as the L307P variant) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain … (more)
Variant summary: BCHE c.1004T>C (p.Leu335Pro, also known as the L307P variant) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain 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 0.00026 in 249654 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (0.00026 vs 0.016), allowing no conclusion about variant significance. c.1004T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyrylcholine Esterase, specifically at a relatively higher frequency in the Vysya Indian community (Manoharan_2006). Numerous homozygous individuals were reported in this community, all of whom had no detectable BChE activity, including 4 individuals from the same family. All measures of BChE activity agreed that there was deficient BChE activity, including Western blotting, labeled BCHE protein, transient expression of the mutant in 293T cell lines and expression in transfected Chinese hamster ovary cells. Molecular dynamics studies showed the negligible activity caused by this mutation is possibly due to its structural instability (David_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyrylcholinesterase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175780.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense variant c.1004T>C(p.Leu335Pro) in BCHE gene has been reported previously in homozygous state in multiple individuals with deficiency Of Butyrylcholine Esteras (Manoharan I, et … (more)
The missense variant c.1004T>C(p.Leu335Pro) in BCHE gene has been reported previously in homozygous state in multiple individuals with deficiency Of Butyrylcholine Esteras (Manoharan I, et al., 2006). The variant has 0.02% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Although insilico analysis show that this mutation possibly due to has structural instability (David SM, et al., 2013), experimental studies are required to prove its Pathogenicity. The amino acid Leucine at position 335 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Leu335Pro in BCHE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
|
|
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Likely pathogenic
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyrylcholinesterase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003818954.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jul 01, 2006)
|
no assertion criteria provided
Method: literature only
|
BUTYRYLCHOLINESTERASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034380.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2018 |
Comment on evidence:
Manoharan et al. (2006) tested 226 plasma samples from a Vysya community in India and found that 9 unrelated individuals had no detectable BCHE activity. … (more)
Manoharan et al. (2006) tested 226 plasma samples from a Vysya community in India and found that 9 unrelated individuals had no detectable BCHE activity. DNA sequencing revealed that all silent BCHE samples were homozygous for a T-C transition at codon 335 in the BCHE gene, resulting in a leu335-to-pro (L335P) substitution. Expression studies in cell culture confirmed that the mutant was expressed at very low levels. The authors noted that 2 of the silent BCHE individuals were 73 and 80 years old, respectively, demonstrating that absence of BCHE is compatible with long life. (less)
|
Comment:
Comment:
The missense variant c.1004T>C(p.Leu335Pro) in BCHE gene has been reported previously in homozygous state in multiple individuals with deficiency Of Butyrylcholine Esteras (Manoharan I, et al., 2006). The variant has 0.02% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Although insilico analysis show that this mutation possibly due to has structural instability (David SM, et al., 2013), experimental studies are required to prove its Pathogenicity. The amino acid Leucine at position 335 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Leu335Pro in BCHE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: BCHE c.1004T>C (p.Leu335Pro, also known as the L307P variant) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain 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 0.00026 in 249654 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (0.00026 vs 0.016), allowing no conclusion about variant significance. c.1004T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyrylcholine Esterase, specifically at a relatively higher frequency in the Vysya Indian community (Manoharan_2006). Numerous homozygous individuals were reported in this community, all of whom had no detectable BChE activity, including 4 individuals from the same family. All measures of BChE activity agreed that there was deficient BChE activity, including Western blotting, labeled BCHE protein, transient expression of the mutant in 293T cell lines and expression in transfected Chinese hamster ovary cells. Molecular dynamics studies showed the negligible activity caused by this mutation is possibly due to its structural instability (David_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The missense variant c.1004T>C(p.Leu335Pro) in BCHE gene has been reported previously in homozygous state in multiple individuals with deficiency Of Butyrylcholine Esteras (Manoharan I, et al., 2006). The variant has 0.02% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Although insilico analysis show that this mutation possibly due to has structural instability (David SM, et al., 2013), experimental studies are required to prove its Pathogenicity. The amino acid Leucine at position 335 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Leu335Pro in BCHE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| An Indian butyrylcholinesterase variant L307P is not structurally stable: a molecular dynamics simulation study. | David SM | Chemico-biological interactions | 2013 | PMID: 23123771 |
| Naturally occurring mutation Leu307Pro of human butyrylcholinesterase in the Vysya community of India. | Manoharan I | Pharmacogenetics and genomics | 2006 | PMID: 16788378 |
Text-mined citations for rs104893684 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.