Variant summary: GLA c.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) of the encoded protein. The variant was absent in 183351 control chromosomes (gnomAD). c.1072_1074delGAG has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Blanch_1996, Topaloglu_1999, Wu_2004, Schafer_2005, Monserrat_2007, Shin_2008, Sawada_2020, Hongo_2020). These data indicate that the variant is very likely to be associated with disease. These publications also reported alpha-galactosidase activity values, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them 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.1072_1074del (p.Glu358del)
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/Likely 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
-
NM_000169.3(GLA):c.1072_1074del (p.Glu358del)
Variation ID: 180844 Accession: VCV000180844.22
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: Xq22.1 X: 101398025-101398027 (GRCh38) [ NCBI UCSC ] X: 100653013-100653015 (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 Jul 24, 2016 Jul 23, 2024 Oct 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.1072_1074del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Glu358del inframe deletion NM_000169.2:c.1070_1072delAGG NP_000160.1:p.Glu358del inframe indel NM_000169.2:c.1072_1074delGAG inframe indel NM_001199973.2:c.300+2570_300+2572del intron variant NM_001199974.2:c.177+6205_177+6207del intron variant NM_001406747.1:c.1195_1197del NP_001393676.1:p.Glu399del inframe deletion NR_164783.1:n.1151_1153del non-coding transcript variant NR_176252.1:n.1002_1004del non-coding transcript variant NR_176253.1:n.1209_1211del non-coding transcript variant NC_000023.11:g.101398027_101398029del NC_000023.10:g.100653015_100653017del NG_007119.1:g.14937_14939del LRG_672:g.14937_14939del LRG_672t1:c.1072_1074del LRG_672p1:p.Glu358del - Protein change
- E358del, E399del
- Other names
- -
- Canonical SPDI
- NC_000023.11:101398024:CTCCT:CT
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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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effect on protein activity; Variation Ontology [ VariO:0053]
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| 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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2023 | RCV000157903.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 12, 2023 | RCV000815405.14 |
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
(Aug 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339433.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
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: SCV002054375.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
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Likely pathogenic
(Aug 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018449.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 03, 2020)
|
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: SCV001361588.2
First in ClinVar: Jun 22, 2020 Last updated: Dec 07, 2020 |
Comment:
Variant summary: GLA c.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) … (more)
Variant summary: GLA c.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) of the encoded protein. The variant was absent in 183351 control chromosomes (gnomAD). c.1072_1074delGAG has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Blanch_1996, Topaloglu_1999, Wu_2004, Schafer_2005, Monserrat_2007, Shin_2008, Sawada_2020, Hongo_2020). These data indicate that the variant is very likely to be associated with disease. These publications also reported alpha-galactosidase activity values, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000955856.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 8807334, 15339079, 15712228, 15713906, 18154965, 26297554). ClinVar contains an entry for this variant (Variation ID: 180844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Glu358 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452068, 12428061, 16595074, 21598360, 24386359, 25382311, 26297554, 26415523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Sep 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000207834.13
First in ClinVar: Feb 24, 2015 Last updated: Jul 23, 2024 |
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18154965, 30116053, 30386727, 12428061, 12512750, 11804208, 15339079, 31956509, 31509825, 28340691, 26415523, 24386359, 21598360, 16595074, 15712228, 26297554, 10666480, 32714835, 32843101, 8807334, 27657681, 33437642, 18698230) (less)
|
Comment:
Comment:
This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 8807334, 15339079, 15712228, 15713906, 18154965, 26297554). ClinVar contains an entry for this variant (Variation ID: 180844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Glu358 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452068, 12428061, 16595074, 21598360, 24386359, 25382311, 26297554, 26415523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18154965, 30116053, 30386727, 12428061, 12512750, 11804208, 15339079, 31956509, 31509825, 28340691, 26415523, 24386359, 21598360, 16595074, 15712228, 26297554, 10666480, 32714835, 32843101, 8807334, 27657681, 33437642, 18698230)
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.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) of the encoded protein. The variant was absent in 183351 control chromosomes (gnomAD). c.1072_1074delGAG has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Blanch_1996, Topaloglu_1999, Wu_2004, Schafer_2005, Monserrat_2007, Shin_2008, Sawada_2020, Hongo_2020). These data indicate that the variant is very likely to be associated with disease. These publications also reported alpha-galactosidase activity values, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 8807334, 15339079, 15712228, 15713906, 18154965, 26297554). ClinVar contains an entry for this variant (Variation ID: 180844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Glu358 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452068, 12428061, 16595074, 21598360, 24386359, 25382311, 26297554, 26415523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18154965, 30116053, 30386727, 12428061, 12512750, 11804208, 15339079, 31956509, 31509825, 28340691, 26415523, 24386359, 21598360, 16595074, 15712228, 26297554, 10666480, 32714835, 32843101, 8807334, 27657681, 33437642, 18698230)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Massive accumulation of globotriaosylceramide in various tissues from a Fabry patient with a high antibody titer against alpha-galactosidase A after 6 years of enzyme replacement therapy. | Hongo K | Molecular genetics and metabolism reports | 2020 | PMID: 32714835 |
| Newborn screening for Fabry disease in the western region of Japan. | Sawada T | Molecular genetics and metabolism reports | 2020 | PMID: 31956509 |
| Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. | Lukas J | Human mutation | 2016 | PMID: 26415523 |
| Identification of mutations in Colombian patients affected with Fabry disease. | Uribe A | Gene | 2015 | PMID: 26297554 |
| Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations. | Riera C | Proteins | 2015 | PMID: 25382311 |
| Comparative study of structural changes caused by different substitutions at the same residue on α-galactosidase A. | Saito S | PloS one | 2013 | PMID: 24386359 |
| A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease. | Wu X | Human mutation | 2011 | PMID: 21598360 |
| Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone. | Shin SH | Pharmacogenetics and genomics | 2008 | PMID: 18698230 |
| Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. | Monserrat L | Journal of the American College of Cardiology | 2007 | PMID: 18154965 |
| 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 |
| Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease. | Schäfer E | Human mutation | 2005 | PMID: 15776423 |
| Pediatric Fabry disease. | Ries M | Pediatrics | 2005 | PMID: 15713906 |
| Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. | Shabbeer J | Human mutation | 2005 | PMID: 15712228 |
| A novel mutation (c. 1072_1074delGAG) in the alpha-galactosidase gene of a Taiwanese family with Fabry disease. | Wu KH | Acta dermato-venereologica | 2004 | PMID: 15339079 |
| Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes. | Germain DP | Molecular medicine (Cambridge, Mass.) | 2002 | PMID: 12428061 |
| Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. | Topaloglu AK | Molecular medicine (Cambridge, Mass.) | 1999 | PMID: 10666480 |
| A novel mutation (E358K) in the alpha-galactosidase A gene detected in a Japanese family with Fabry disease. | Miyazaki T | Human mutation | 1998 | PMID: 9452068 |
| A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. | Blanch LC | Human mutation | 1996 | PMID: 8807334 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
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Text-mined citations for rs730880453 ...
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.