Variant summary: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183379 control chromosomes (gnomAD). c.640-1G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2006, Sawada_2015, Pensabene_2016, and Frabasil_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.640-1G>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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.640-1G>A
Variation ID: 597544 Accession: VCV000597544.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398947 (GRCh38) [ NCBI UCSC ] X: 100653935 (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 Dec 16, 2018 Feb 14, 2024 Mar 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.640-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001199973.2:c.300+3490C>T intron variant NM_001199974.2:c.177+7125C>T intron variant NM_001406747.1:c.763-1G>A splice acceptor NM_001406748.1:c.640-1G>A splice acceptor NC_000023.11:g.101398947C>T NC_000023.10:g.100653935C>T NG_007119.1:g.14017G>A LRG_672:g.14017G>A LRG_672t1:c.640-1G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000023.11:101398946:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7 | 1257 | |
| RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1295 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2019 | RCV000733701.9 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2023 | RCV000781421.15 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jun 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861794.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: mixed
|
|
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Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054426.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
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Pathogenic
(Dec 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813226.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919439.2
First in ClinVar: Jun 02, 2019 Last updated: May 13, 2023 |
Comment:
Variant summary: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183379 control chromosomes (gnomAD). c.640-1G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2006, Sawada_2015, Pensabene_2016, and Frabasil_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024327.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000962384.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 16595074, 26631895). In at least one individual the variant was observed … (more)
Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 16595074, 26631895). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 597544). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the GLA 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 GLA are known to be pathogenic (PMID: 10666480, 12175777). (less)
|
Comment:
Comment:
Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 16595074, 26631895). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 597544). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the GLA 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 GLA are known to be pathogenic (PMID: 10666480, 12175777).
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: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183379 control chromosomes (gnomAD). c.640-1G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2006, Sawada_2015, Pensabene_2016, and Frabasil_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Disruption of this splice site has been observed in individual(s) with Fabry disease (PMID: 16595074, 26631895). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 597544). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the GLA 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 GLA are known to be pathogenic (PMID: 10666480, 12175777).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence of Fabry disease in male dialysis patients: Argentinean screening study. | Frabasil J | JIMD reports | 2019 | PMID: 31392112 |
| Gastrointestinal Symptoms of Patients with Fabry Disease. | Pensabene L | Gastroenterology research and practice | 2016 | PMID: 26880903 |
| A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman. | Sawada J | Internal medicine (Tokyo, Japan) | 2015 | PMID: 26631895 |
| Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. | Shabbeer J | Human genomics | 2006 | PMID: 16595074 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. | Shabbeer J | Molecular genetics and metabolism | 2002 | PMID: 12175777 |
| Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. | Topaloglu AK | Molecular medicine (Cambridge, Mass.) | 1999 | PMID: 10666480 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs398123216 ...
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 Sep 29, 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.