ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.681T>G (p.Asn227Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000157.4(GBA1):c.681T>G (p.Asn227Lys)
Variation ID: 93458 Accession: VCV000093458.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155238214 (GRCh38) [ NCBI UCSC ] 1: 155208005 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 29, 2015 Feb 20, 2024 Aug 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.681T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Asn227Lys missense NM_001005741.3:c.681T>G NP_001005741.1:p.Asn227Lys missense NM_001005742.3:c.681T>G NP_001005742.1:p.Asn227Lys missense NM_001171811.2:c.420T>G NP_001165282.1:p.Asn140Lys missense NM_001171812.2:c.534T>G NP_001165283.1:p.Asn178Lys missense NC_000001.11:g.155238214A>C NC_000001.10:g.155208005A>C NG_009783.1:g.11484T>G NG_042867.1:g.4676A>C P04062:p.Asn227Lys - Protein change
- N227K, N140K, N178K
- Other names
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- Canonical SPDI
- NC_000001.11:155238213:A:C
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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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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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GBA1 | - | - |
GRCh38 GRCh38 GRCh37 |
31 | 396 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 352 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2023 | RCV000079353.8 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004130.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 13, 2023 | RCV001249030.4 |
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
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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
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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
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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. |
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Pathogenic
(May 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000111223.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001162861.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(Jan 29, 2020)
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criteria provided, single submitter
Method: curation
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Gaucher disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422960.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Asn227Lys variant in GBA has been reported in 5 individuals with Gaucher disease (PMID: 9683600, 23719189, 10649495, 25435509, 27872820) and has been identified in … (more)
The p.Asn227Lys variant in GBA has been reported in 5 individuals with Gaucher disease (PMID: 9683600, 23719189, 10649495, 25435509, 27872820) and has been identified in 0.002% (2/113716) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs381418). Please note that 1 additional individual in gnomAD has this change in phase with an additional nucleotide change, resulting in a multinucleotide variant (p.Asn227Arg). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93458) as pathogenic by EGL Genetic Diagnostics. The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher disease based on null or very low beta-glucosidase levels consistent with disease (PMID: 27872820, 9683600). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asn227Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 26743617, 24022302). The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the p.Asn227Lys variant is pathogenic (VariationID: 4288, 4290; PMID: 9683600, 23719189, 27872820). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM5_supporting, PP4 (Richards 2015). (less)
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Pathogenic
(Feb 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844619.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: GBA c.681T>G (p.Asn227Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: GBA c.681T>G (p.Asn227Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251364 control chromosomes. c.681T>G has been reported in the literature in individuals affected with Gaucher Disease. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004565297.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The GBA c.681T>G; p.Asn227Lys variant (rs381418), also known as Asn188Lys for legacy nomenclature, is reported in multiple individuals with Gaucher disease or GBA-associated Parkinson's disease … (more)
The GBA c.681T>G; p.Asn227Lys variant (rs381418), also known as Asn188Lys for legacy nomenclature, is reported in multiple individuals with Gaucher disease or GBA-associated Parkinson's disease (Amico 2016, Germain 1998, Guedes 2017, Kim 2020, Ortiz-Cabrera 2016). This variant is also reported in ClinVar (Variation ID: 93458). It is only found on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.587). A different variant at this codon, p.Asn227Ser, has also been reported in association with Gaucher disease and is considered to be pathogenic (see ClinVar Variation ID: 4314). Based on available information, the p.Asn227Lys variant is considered to be pathogenic. References: Amico G et al. MLPA-based approach for initial and simultaneous detection of GBA deletions and recombinant alleles in patients affected by Gaucher Disease. Mol Genet Metab. 2016 Dec;119(4):329-337. PMID: 27802905. Germain DP et al. Exhaustive screening of the acid beta-glucosidase gene, by fluorescence-assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease. Am J Hum Genet. 1998 Aug;63(2):415-27. PMID: 9683600. Guedes LC et al. Serum lipid alterations in GBA-associated Parkinson's disease. Parkinsonism Relat Disord. 2017 Nov;44:58-65. PMID: 28890071. Kim YM et al. The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects. Orphanet J Rare Dis. 2020 Nov 11;15(1):318. PMID: 33176831. Ortiz-Cabrera NV et al. Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundacion Jimenez Diaz. Mol Genet Metab Rep. 2016 Nov 13;9:79-85. PMID: 27872820. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models. | Costa R | Human molecular genetics | 2020 | PMID: 31816052 |
Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz. | Ortiz-Cabrera NV | Molecular genetics and metabolism reports | 2016 | PMID: 27872820 |
The clinical management of Type 2 Gaucher disease. | Weiss K | Molecular genetics and metabolism | 2015 | PMID: 25435509 |
A common and two novel GBA mutations in Thai patients with Gaucher disease. | Tammachote R | Journal of human genetics | 2013 | PMID: 23719189 |
Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. | Stone DL | Human mutation | 2000 | PMID: 10649495 |
Exhaustive screening of the acid beta-glucosidase gene, by fluorescence-assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease. | Germain DP | American journal of human genetics | 1998 | PMID: 9683600 |
Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. | Latham TE | DNA and cell biology | 1991 | PMID: 1899336 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/339c611d-dfad-41f8-8030-47154ce116f8 | - | - | - | - |
Text-mined citations for rs381418 ...
HelpRecord last updated Mar 30, 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.