NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 12204005, 25127542, 1558964, 11933202 and 20729108. Classification of NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.115+1G>A
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.
(20)
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
20
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000157.4(GBA1):c.115+1G>A
Variation ID: 93445 Accession: VCV000093445.86
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 155240629 (GRCh38) [ NCBI UCSC ] 1: 155210420 (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 Apr 4, 2013 Oct 20, 2024 Jul 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000157.4:c.115+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001005741.3:c.115+1G>A splice donor NM_001005742.2:c.115+1G>A NM_001005742.3:c.115+1G>A splice donor NM_001171811.2:c.-146-552G>A intron variant NM_001171812.2:c.115+1G>A splice donor NC_000001.11:g.155240629C>T NC_000001.10:g.155210420C>T NG_009783.1:g.9069G>A - Protein change
- -
- Other names
-
IVS2DS+1G-A
IVS2DS, G-A, +1
- Canonical SPDI
- NC_000001.11:155240628:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00006
- 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. |
|||
| GBA1 | - | - |
GRCh38 GRCh38 GRCh37 |
32 | 405 | |
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 (1) |
no assertion criteria provided
|
Jan 1, 2000 | RCV000004546.13 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2020 | RCV000032094.16 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 9, 2019 | RCV000177098.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762856.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004137.9 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2021 | RCV001253701.13 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jul 25, 2024 | RCV000790724.47 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2017 | RCV004019534.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Gaucher disease type I
Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001162868.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Gaucher disease type I
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194067.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for … (more)
NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 12204005, 25127542, 1558964, 11933202 and 20729108. Classification of NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Likely pathogenic
(Sep 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinson disease, late-onset
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429549.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinson disease, late-onset
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001994778.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
|
|
|
Pathogenic
(Apr 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503250.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Oct 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000935506.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with Gaucher disease and/or Parkinson disease (PMID: 20816920, 23430873, 25653295, 26117366, 27682613). This variant is also known as IVS2+1. ClinVar contains an entry for this variant (Variation ID: 93445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003825838.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002756316.2
First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024 |
Comment:
The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. … (more)
The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. This mutation has been reported in multiple patients with Gaucher disease, confirmed with decreased beta-glucosidase activity (Beutler E et al. Blood, 1992 Apr;79:1662-6; Yoshida S et al. Pediatr Int, 2016 Sep;58:946-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198013.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Aug 11, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Gaucher disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697575.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment:
Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this … (more)
Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant eliminates the splicing donor site, which has been confirmed in one patient using cDNA sequencing. This variant has been reported in numerous patients with Gaucher disease. This variant was found in 14/121336 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lewy body dementia
Parkinson disease, late-onset Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Gaucher disease perinatal lethal
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893216.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Sep 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228922.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 7
Sex: mixed
|
|
|
Pathogenic
(May 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinson disease, late-onset
Affected status: yes
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV001652796.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
|
|
|
Pathogenic
(Jan 13, 2020)
|
criteria provided, single submitter
Method: curation
|
Gaucher disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422684.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in … (more)
The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in 0.019% (2/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886460). 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: 93445) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the c.115+1G>A variant is pathogenic (VariationID: 4288, 4290; PMID: 10649495, 23430873). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that the variant will cause loss-of-function and the occurrences of the variant in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). (less)
|
|
|
Pathogenic
(Jul 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001763816.4
First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 20816920, 25653295, 25525159, 21228398, 1558964, 23430873, 21700325, 35861108, 33473340, 26689913, 26117366, 27682613, 31561936, 33176831, 36637080, 32191290, 33402667, 33301762, 34867278, 34930372, 35747619, 34308104, 35242582, 35845720, 37198191, 35639160, 36879366, 33972609, 32613234) (less)
|
|
|
Pathogenic
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247925.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Comment:
GBA1: PVS1, PS4:Moderate, PM2:Supporting
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Jan 01, 2000)
|
no assertion criteria provided
Method: literature only
|
GAUCHER DISEASE, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024719.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017 |
Comment on evidence:
In a survey of 100 unrelated Jewish patients with type I Gaucher disease (230800), Beutler et al. (1992) found that 5 of the mutant GBA … (more)
In a survey of 100 unrelated Jewish patients with type I Gaucher disease (230800), Beutler et al. (1992) found that 5 of the mutant GBA alleles resulted from a splice site mutation in intron 2 (IVS2DS+1G-A), resulting in skipping of exon 2. The phenotype was associated with earlier onset and more severe disease compared to the common N370S mutation (606463.0003). He and Grabowski (1992) identified the IVS2DS+1G-A transition in a moderately affected 9-year-old Ashkenazi Jewish patient with type I Gaucher disease. The transition was found also at the corresponding exon/intron boundary of the highly homologous pseudogene. This splicing mutation accounted for about 3.4% of the Gaucher disease alleles in the Ashkenazi Jewish population. Stone et al. (2000) identified compound heterozygosity for the IVS2DS+1G-A mutation and L444P (606463.0001) in 2 unrelated patients with type II Gaucher disease (230900). (less)
|
|
|
Pathogenic
(Jan 01, 2000)
|
no assertion criteria provided
Method: literature only
|
GAUCHER DISEASE, TYPE II
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024720.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017 |
Comment on evidence:
In a survey of 100 unrelated Jewish patients with type I Gaucher disease (230800), Beutler et al. (1992) found that 5 of the mutant GBA … (more)
In a survey of 100 unrelated Jewish patients with type I Gaucher disease (230800), Beutler et al. (1992) found that 5 of the mutant GBA alleles resulted from a splice site mutation in intron 2 (IVS2DS+1G-A), resulting in skipping of exon 2. The phenotype was associated with earlier onset and more severe disease compared to the common N370S mutation (606463.0003). He and Grabowski (1992) identified the IVS2DS+1G-A transition in a moderately affected 9-year-old Ashkenazi Jewish patient with type I Gaucher disease. The transition was found also at the corresponding exon/intron boundary of the highly homologous pseudogene. This splicing mutation accounted for about 3.4% of the Gaucher disease alleles in the Ashkenazi Jewish population. Stone et al. (2000) identified compound heterozygosity for the IVS2DS+1G-A mutation and L444P (606463.0001) in 2 unrelated patients with type II Gaucher disease (230900). (less)
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Gaucher disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086486.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Gaucher disease
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000054468.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 29, 2022 |
|
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Comment:
Comment:
This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with Gaucher disease and/or Parkinson disease (PMID: 20816920, 23430873, 25653295, 26117366, 27682613). This variant is also known as IVS2+1. ClinVar contains an entry for this variant (Variation ID: 93445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. This mutation has been reported in multiple patients with Gaucher disease, confirmed with decreased beta-glucosidase activity (Beutler E et al. Blood, 1992 Apr;79:1662-6; Yoshida S et al. Pediatr Int, 2016 Sep;58:946-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant eliminates the splicing donor site, which has been confirmed in one patient using cDNA sequencing. This variant has been reported in numerous patients with Gaucher disease. This variant was found in 14/121336 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in 0.019% (2/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886460). 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: 93445) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the c.115+1G>A variant is pathogenic (VariationID: 4288, 4290; PMID: 10649495, 23430873). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that the variant will cause loss-of-function and the occurrences of the variant in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 20816920, 25653295, 25525159, 21228398, 1558964, 23430873, 21700325, 35861108, 33473340, 26689913, 26117366, 27682613, 31561936, 33176831, 36637080, 32191290, 33402667, 33301762, 34867278, 34930372, 35747619, 34308104, 35242582, 35845720, 37198191, 35639160, 36879366, 33972609, 32613234)
Comment:
GBA1: PVS1, PS4:Moderate, PM2:Supporting
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:
NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 12204005, 25127542, 1558964, 11933202 and 20729108. Classification of NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with Gaucher disease and/or Parkinson disease (PMID: 20816920, 23430873, 25653295, 26117366, 27682613). This variant is also known as IVS2+1. ClinVar contains an entry for this variant (Variation ID: 93445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. This mutation has been reported in multiple patients with Gaucher disease, confirmed with decreased beta-glucosidase activity (Beutler E et al. Blood, 1992 Apr;79:1662-6; Yoshida S et al. Pediatr Int, 2016 Sep;58:946-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant eliminates the splicing donor site, which has been confirmed in one patient using cDNA sequencing. This variant has been reported in numerous patients with Gaucher disease. This variant was found in 14/121336 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in 0.019% (2/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886460). 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: 93445) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the c.115+1G>A variant is pathogenic (VariationID: 4288, 4290; PMID: 10649495, 23430873). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that the variant will cause loss-of-function and the occurrences of the variant in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 20816920, 25653295, 25525159, 21228398, 1558964, 23430873, 21700325, 35861108, 33473340, 26689913, 26117366, 27682613, 31561936, 33176831, 36637080, 32191290, 33402667, 33301762, 34867278, 34930372, 35747619, 34308104, 35242582, 35845720, 37198191, 35639160, 36879366, 33972609, 32613234)
Comment:
GBA1: PVS1, PS4:Moderate, PM2:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Gaucher Disease. | Adam MP | - | 2023 | PMID: 20301446 |
| High-frequency component in flash visual evoked potentials in type 3 Gaucher disease. | Oguri M | Brain & development | 2020 | PMID: 31561936 |
| Prenatal diagnosis of Gaucher disease using next-generation sequencing. | Yoshida S | Pediatrics international : official journal of the Japan Pediatric Society | 2016 | PMID: 27682613 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
| Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. | Alcalay RN | Brain : a journal of neurology | 2015 | PMID: 26117366 |
| Differential effects of severe vs mild GBA mutations on Parkinson disease. | Gan-Or Z | Neurology | 2015 | PMID: 25653295 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. | Sechi A | Molecular genetics and metabolism | 2014 | PMID: 25127542 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| A twelve-year follow-up study on a case of early-onset parkinsonism preceding clinical manifestation of Gaucher disease. | Machaczka M | JIMD reports | 2012 | PMID: 23430873 |
| Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. | Mazzulli JR | Cell | 2011 | PMID: 21700325 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| Clinical and genetic characteristics of Korean patients with Gaucher disease. | Jeong SY | Blood cells, molecules & diseases | 2011 | PMID: 20729108 |
| Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease. | Dos Santos AV | Neuroscience letters | 2010 | PMID: 20816920 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients. | Filocamo M | Human mutation | 2002 | PMID: 12204005 |
| The identification of eight novel glucocerebrosidase (GBA) mutations in patients with Gaucher disease. | Orvisky E | Human mutation | 2002 | PMID: 11933202 |
| Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of 11 novel mutations. | Alfonso P | Blood cells, molecules & diseases | 2001 | PMID: 11783951 |
| Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. | Koprivica V | American journal of human genetics | 2000 | PMID: 10796875 |
| Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. | Stone DL | Human mutation | 2000 | PMID: 10649495 |
| Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease. | Grace ME | The Journal of clinical investigation | 1999 | PMID: 10079102 |
| Identification and expression of acid beta-glucosidase mutations causing severe type 1 and neurologic type 2 Gaucher disease in non-Jewish patients. | Grace ME | The Journal of clinical investigation | 1997 | PMID: 9153297 |
| Gaucher disease: new molecular approaches to diagnosis and treatment. | Beutler E | Science (New York, N.Y.) | 1992 | PMID: 1589760 |
| Mutations in Jewish patients with Gaucher disease. | Beutler E | Blood | 1992 | PMID: 1558964 |
| Gaucher disease: A G+1----A+1 IVS2 splice donor site mutation causing exon 2 skipping in the acid beta-glucosidase mRNA. | He GS | American journal of human genetics | 1992 | PMID: 1415223 |
| Complex alleles of the acid beta-glucosidase gene in Gaucher disease. | Latham T | American journal of human genetics | 1990 | PMID: 2349952 |
| Comparison of RNase A, a chemical cleavage and GC-clamped denaturing gradient gel electrophoresis for the detection of mutations in exon 9 of the human acid beta-glucosidase gene. | Theophilus BD | Nucleic acids research | 1989 | PMID: 2508065 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
| http://www.ncbi.nlm.nih.gov/books/NBK1269/ | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e7a68bbd-f229-4b17-9460-5d1fc10edad4 | - | - | - | - |
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Text-mined citations for rs104886460 ...
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Record last updated Nov 03, 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.