ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.640-801G>A
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.
Pathogenic(11); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.640-801G>A
Variation ID: 10768 Accession: VCV000010768.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101399747 (GRCh38) [ NCBI UCSC ] X: 100654735 (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 Jan 31, 2015 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.640-801G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001199973.2:c.300+4290C>T intron variant NM_001199974.2:c.177+7925C>T intron variant NR_164783.1:n.715G>A non-coding transcript variant NC_000023.11:g.101399747C>T NC_000023.10:g.100654735C>T NG_007119.1:g.13217G>A LRG_672:g.13217G>A LRG_672t1:c.639+919G>A - Protein change
- Other names
- IVS4+919G>A
- IVS4AS, G-A, -4
- Canonical SPDI
- NC_000023.11:101399746: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.
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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 | ||
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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
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 |
6 | 1239 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1270 |
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. |
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Uncertain significance (1) |
no assertion criteria provided
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Apr 1, 2002 | RCV000011515.7 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 17, 2024 | RCV000154318.24 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2023 | RCV000769537.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 3, 2018 | RCV000844706.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2023 | RCV000728949.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2022 | RCV002362578.3 |
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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Pathogenic
(Aug 24, 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: SCV000856576.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Fabry disease (X-linked inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203980.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The c.639+919G>A variant in GLA (also described as c.640-801G>A in the literatur e) has been reported in at least 6 individuals with a later-onset, cardiac … (more)
The c.639+919G>A variant in GLA (also described as c.640-801G>A in the literatur e) has been reported in at least 6 individuals with a later-onset, cardiac varia nt of Fabry disease (Ishii 2002) and in many individuals with hypertrophic cardi omyopathy (HCM) or left ventricular hypertrophy (LVH), all of whom exhibited red uced GLA enzyme activity levels (Ishii 2002, Lin 2009, Lin 2010, Hsu 2016, Kubo 2017). This variant has also been identified by our laboratory in 4 Asian indivi duals with HCM or Fabry disease, and segregated with disease in 3 affected relat ives (2 with Fabry disease and 1 with reduced GLA activity). This variant has be en also been identified in 1/1041 of Asian chromosomes (a hemizygous male) by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs199473684). Functional studies have shown that the c.639+919G>A variant result s in the accumulation of lamellar bodies and glycosphingolipids in induced pluri potent stem cell cardiomyocytes from a patient with Fabry disease (Chou 2017). I n addition, mRNA slicing studies have shown that this variant leads to abnormal splicing, resulting in the introduction of an additional 57 nucleotides into the GLA transcript, ultimately leading to a truncated protein (Ischii 2002, Palhais 2016, Chang 2017). In summary, the c.639+919G>A variant meets criteria to be cl assified as pathogenic for Fabry disease in an X-linked manner based upon presen ce in multiple affected individuals, functional and segregation studies. ACMG/AM P Criteria applied (Richards 2015): PS3; PS4; PP1. (less)
Number of individuals with the variant: 10
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004839054.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. … (more)
This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823). These studies have shown that the alternate transcript was present at low levels in most normal tissues and is significantly increased in cells from carrier individuals affected with Fabry disease. This variant has been reported in over forty males of East Asian ancestry affected with mild, late-onset Fabry disease (PMID: 11828341, 20031620, 32246049, 36013057). This variant has also been observed in individuals affected with cardiomyopathy, who showed reduced GLA enzyme activity (PMID: 20031620, 25611685, 30731207, 31028938) and in an individual affected with left ventricular hypertrophy (PMID: 35743592). This variant has been reported to segregate with disease in multiple families affected with Fabry disease or hypertrophic cardiomyopathy (ClinVar SCV000203980.4). Literature has reported the absence of this variant in 230 unaffected control males and 149 unaffected control females (PMID: 11828341, 19621417). This variant has been identified in 1/22077 chromosomes by the Genome Aggregation Database (gnomAD; low coverage region). Large newborn screening studies have shown that this variant is highly prevalent in the Taiwanese population with up to 1/875 males and 1/399 females being carriers (PMID: 19621417, 20031620, 22437327). Mean enzyme activities in the male and female carriers were 23% and 55% of normal mean values, respectively (PMID: 22437327). Loss of GLA function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927901.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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Pathogenic
(Mar 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001788703.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Has been reported as a common variant in Taiwanese and Japanese populations in association with reduced GLA enzyme activity levels and Fabry late-onset cardiac phenotype … (more)
Has been reported as a common variant in Taiwanese and Japanese populations in association with reduced GLA enzyme activity levels and Fabry late-onset cardiac phenotype (for examples, see Ishii et al., 2002; Lin et al., 2010; Chien et al., 2012; Hsu et al., 2016; Sakuraba et al., 2018; of note, this variant is also reported as c.639+919 G>A due to the use of alternate nomenclature); Has been observed in 1/1000 alleles from individuals of Asian background, including one hemizygous individual, in large population cohorts (Lek et al., 2016); In vitro functional studies have shown that c.640-801 G>A creates a cryptic splice site that causes abnormal gene splicing through introduction of an additional 57 nucleotides into the GLA transcript (Ishii et al., 2002; Palhais et al., 2016; Chang et al., 2017); Additional functional studies have shown that this variant is associated with approximately 10% residual alpha-galactosidase activity in patient lymphoblasts (Ishii et al, 2002); Reported in ClinVar as pathogenic (ClinVar Variant ID# 10768; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33204599, 32246049, 32150461, 31447099, 30477121, 31956509, 30662066, 30666049, 30386727, 30380558, 30103270, 28082092, 29215092, 27554049, 28430823, 28377241, 20031620, 11828341, 20821055, 28322587, 27931613, 26869469, 25611685, 24980630, 19621417, 19823873, 24055776, 22437327, 27595546) (less)
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Pathogenic
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002014858.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: The variant c.640-801G>A is located in intron 4 of the GLA gene. Several in vitro studies demonstrated, that the variant activates a cryptic … (more)
Variant summary: The variant c.640-801G>A is located in intron 4 of the GLA gene. Several in vitro studies demonstrated, that the variant activates a cryptic exon between exon 4 and 5 that results in the insertion of 57 intronic nucleotide, leading to a premature stop codon (Ishii 2002, Chiang 2017, Chang 2017). However, the variant had an incomplete effect on splicing, as the full length product was also detected. Though the truncated variant-protein had no enzyme activity (Ishii 2002), since the normal transcript was also present, it resulted in some residual enzyme activity in samples from male individuals carrying the variant (Ishii 2002, Lin 2010, Chien 2012, Chang 2017). The variant allele was found in 1/22077 control chromosomes in the genome dataset of gnomAD database (detected in an East Asian individual). c.640-801G>A has been reported in the literature in several individuals affected with the Cardiac Variant of Fabry Disease (FD) (e.g. Ishii 2002, Lin 2010, Hsu 2019), but was also found in controls, especially in East Asian populations, where the variant was observed with a relatively high frequency (~0.0011) in Taiwanese individuals during newborn screening and in healthy adult controls (Chien 2012, Chiang 2017). Though this frequency is higher than predicted for a pathogenic variant in the GLA gene, a recent study indicated that the variant might result in a latent disease progression, with Fabry Disease-associated late onset cardiomyopathy that in many cases can only be detected with more sensitive diagnostic methods or much later in life (Hsu 2019). These authors also suggested that the prevalence of late-onset FD might be much higher than previously expected. In addition, another recent study proposed a multifactorial model, consisting of combinations of multiple variants in conjunction with other organ-related or environmental factors as contributing to the associated cardiac complications and the natural history of disease progression related to this variant (Juang 2019). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; eight classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant causes a cryptic splice-mutation resulting in decreased enzyme activity, and although it is relatively common in some East Asian subpopulations, it was reported in several individuals with late-onset cardiac FD phenotype; therefore it was classified as pathogenic. (less)
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422791.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The c.639+919G>A variant in GLA has been reported in at least 6 individuals with Fabry disease, segregated with disease in 3 affected relatives from 1 … (more)
The c.639+919G>A variant in GLA has been reported in at least 6 individuals with Fabry disease, segregated with disease in 3 affected relatives from 1 family (PMID:29215092, 25611685, 22437327,19621417, 20821055, 20031620,11828341), and has been identified in 0.1% (1/1000) of East Asian chromosomes, including a single hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473684). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as a VUS by OMIM and as pathogenic by the Laboratory for Molecular Medicine (Partners Healthcare), Invitae, EGL Clinical Diagnostics, and GeneReviews (ID:10768). In vitro functional studies provide some evidence that the c.639+919G>A variant may impact protein function as a result of alternative splicing and decreased enzyme activity (PMID:11828341, 28430823, 27595546). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype consistent with disease (PMID: 25611685, 22437327,19621417, 20821055, 20031620,11828341). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PP1, PP4 (Richards 2015). (less)
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Pathogenic
(Sep 28, 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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Revvity Omics, Revvity
Accession: SCV002024291.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900932.4 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Pathogenic
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001734431.3
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. … (more)
This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823). These studies have shown that the alternate transcript was present at low levels in most normal tissues and is significantly increased in cells from carrier individuals affected with Fabry disease. This variant has been reported in over forty males of East Asian ancestry affected with mild, late-onset Fabry disease (PMID: 11828341, 20031620, 32246049, 36013057). This variant has also been observed in individuals affected with cardiomyopathy, who showed reduced GLA enzyme activity (PMID: 20031620, 25611685, 30731207, 31028938) and in an individual affected with left ventricular hypertrophy (PMID: 35743592). This variant has been reported to segregate with disease in multiple families affected with Fabry disease or hypertrophic cardiomyopathy (ClinVar SCV000203980.4). Literature has reported the absence of this variant in 230 unaffected control males and 149 unaffected control females (PMID: 11828341, 19621417). This variant has been identified in 1/22077 chromosomes by the Genome Aggregation Database (gnomAD; low coverage region). Large newborn screening studies have shown that this variant is highly prevalent in the Taiwanese population with up to 1/875 males and 1/399 females being carriers (PMID: 19621417, 20031620, 22437327). Mean enzyme activities in the male and female carriers were 23% and 55% of normal mean values, respectively (PMID: 22437327). Loss of GLA function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000748692.8
First in ClinVar: Jan 31, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 4 of the GLA gene. It does not directly change the encoded amino acid sequence of the GLA protein. … (more)
This sequence change falls in intron 4 of the GLA gene. It does not directly change the encoded amino acid sequence of the GLA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs199473684, gnomAD 0.1%). This variant has been observed in individual(s) with Fabry disease and hypertrophic cardiomyopathy (PMID: 11828341, 19621417, 20031620, 22437327, 25611685). It is commonly reported in individuals of Taiwanese ancestry (PMID: 27931613). This variant is also known as IVS4+919G>A. ClinVar contains an entry for this variant (Variation ID: 10768). Studies have shown that this variant results in insertion of 57bp pseudoexon sequence in intron 4 and introduces a premature termination codon (PMID: 11828341, 27595546, 28430823). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002658884.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.640-801G>A intronic pathogenic mutation results from a G to A substitution 801 nucleotides upstream from coding exon 5 in the GLA gene. This alteration … (more)
The c.640-801G>A intronic pathogenic mutation results from a G to A substitution 801 nucleotides upstream from coding exon 5 in the GLA gene. This alteration (also referred to as IVS4+919G>A, c.936+919G>A or c.639+919G>A in the literature) has been detected in many individuals from Asian populations with reduced alpha-galactosidase A enzyme activity on newborn screen, and has also been detected in adult males and females with reduced enzyme activity reported to have late-onset, primarily cardiac variant Fabry disease with presentation typically after 40 years of age, although the frequency of this variant suggests it exhibits reduced penetrance (Ishii S et al. Am J Hum Genet. 2002;70:994-1002; Hwu WL et al. Hum Mutat. 2009;30:1397-405; Lin HY et al. Circ Cardiovasc Genet. 2009;2:450-6; Lin HY et al. J Inherit Metab Dis. 2010;33:619-24; Chien YH et al. Mol Med. 2012;18:780-4; Hsu TR et al. Orphanet J Rare Dis. 2014;9:96; Kubo T et al. J Cardiol. 2017;69:302-307; Sakuraba H et al. Mol Genet Metab Rep. 2018;17:73-79). In a study of patient-derived induced pluripotent stem cells, cardiomyocytes with this alteration recapitulated the abnormal cardiac phenotype (Chou SJ et al. Int J Cardiol. 2017;232:255-263). This alteration has been demonstrated to result in aberrant splicing, leading to increased expression of a transcript including a portion of intron 4 and the introduction of a premature stop codon (Ishii S et al. Am J Hum Genet. 2002 Apr;70:994-1002; Palhais B et al. Mol Genet Metab. 2016;119:258-269; Chang WH et al. PLoS ONE. 2017;12:e0175929). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(Apr 01, 2002)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031747.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 20, 2017 |
Comment on evidence:
This variant, previously titled FABRY DISEASE, CARDIAC VARIANT, has been reclassified based on the findings of Chiang et al. (2017). During the course of mutation … (more)
This variant, previously titled FABRY DISEASE, CARDIAC VARIANT, has been reclassified based on the findings of Chiang et al. (2017). During the course of mutation analysis of a patient with the cardiac form of Fabry disease (see 301500) who had residual enzyme activity 9.1% of normal, Ishii et al. (2002) were unable to identify any mutation in the exonic or flanking intronic regions of the GLA gene. By RT-PCR of the RNA and direct sequencing of the RT-PCR product, they found an insertion between exons 4 and 5. To characterize further the abnormal splicing, they sequenced intron 4 (nucleotides 8413-10130) of the GLA gene and identified a G-to-A transition at nucleotide 9331 (IVS4+919G-A). This change was not found in 100 unaffected Japanese males. The mutation in the middle of the intron increased the recognition of a normally weak splice site, resulting in the insertion of an additional sequence into the GLA transcript and leading to the cardiac phenotype of Fabry disease. Chiang et al. (2017) screened for the IVS4+919G-A variant in the Taiwanese population, including 3,268 controls, 3,949 patients from a type 2 diabetes cohort, and 649 patients from heart disease cohorts (heart failure, atrial fibrillation, ventricular tachycardia, and coronary artery disease). In the control sample, 4 males and 2 females carried the variant and only 1 male, who reportedly had a history of heavy smoking and drinking, had heart disease; none of 80 controls who reportedly had cardiomyopathy carried the variant. In the diabetes cohort, 1 of 11 patients who carried the variant had overt heart disease. Among the heart disease cohorts, only 1 patient carried the variant. The authors found that the incidence of the variant in their population was 1/409. (less)
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Pathogenic
(Nov 30, 2020)
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no assertion criteria provided
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002081343.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Fabry disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000494669.2
First in ClinVar: Jan 31, 2015 Last updated: Oct 01, 2022 |
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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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Fabry Disease. | Adam MP | - | 2024 | PMID: 20301469 |
Renoprotective Effect of Agalsidase Alfa: A Long-Term Follow-Up of Patients with Fabry Disease. | Cybulla M | Journal of clinical medicine | 2022 | PMID: 36013057 |
Unexplained Left Ventricular Hypertrophy with Symptomatic High-Grade Atrioventricular Block in Elderly Patients: A Case Report. | Yu TP | Journal of clinical medicine | 2022 | PMID: 35743592 |
The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago. | Liang KH | Journal of human genetics | 2020 | PMID: 32246049 |
Adopting High-Resolution Allele Frequencies Substantially Expedites Variant Interpretation in Genetic Diagnostic Laboratories. | Ghani M | The Journal of molecular diagnostics : JMD | 2019 | PMID: 31028938 |
Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting. | Daoud H | The Journal of molecular diagnostics : JMD | 2019 | PMID: 30731207 |
Fabry disease cardiac variant IVS4+919 G>A is associated with multiple cardiac gene variants in patients with severe cardiomyopathy and fatal arrhythmia. | Juang JJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30662066 |
Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulations before the occurrence of typical pathological changes in the endomyocardial biopsies of Fabry disease patients. | Hsu MJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29875425 |
Fabry disease in a Japanese population-molecular and biochemical characteristics. | Sakuraba H | Molecular genetics and metabolism reports | 2018 | PMID: 30386727 |
Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center. | Lin CJ | Kidney & blood pressure research | 2018 | PMID: 30380558 |
Improvement in the sensitivity of newborn screening for Fabry disease among females through the use of a high-throughput and cost-effective method, DNA mass spectrometry. | Lu YH | Journal of human genetics | 2018 | PMID: 29215092 |
Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease. | Chang WH | PloS one | 2017 | PMID: 28430823 |
Genetic epidemiological study doesn't support GLA IVS4+919G>A variant is a significant mutation in Fabry disease. | Chiang HL | Molecular genetics and metabolism | 2017 | PMID: 28377241 |
Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease. | Chou SJ | International journal of cardiology | 2017 | PMID: 28082092 |
Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy. | Kubo T | Journal of cardiology | 2017 | PMID: 27554049 |
Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation. | Hsu TR | Journal of the American College of Cardiology | 2016 | PMID: 27931613 |
The prevalent deep intronic c. 639+919 G>A GLA mutation causes pseudoexon activation and Fabry disease by abolishing the binding of hnRNPA1 and hnRNP A2/B1 to a splicing silencer. | Palhais B | Molecular genetics and metabolism | 2016 | PMID: 27595546 |
Brain MR Imaging Findings of Cardiac-Type Fabry Disease with an IVS4+919G>A Mutation. | Lee HJ | AJNR. American journal of neuroradiology | 2016 | PMID: 26869469 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4 + 919G > A). | Hsu TR | Orphanet journal of rare diseases | 2014 | PMID: 24980630 |
Lyso-globotriaosylsphingosine (lyso-Gb3) levels in neonates and adults with the Fabry disease later-onset GLA IVS4+919G>A mutation. | Chien YH | Journal of inherited metabolic disease | 2013 | PMID: 23109060 |
Fabry disease: incidence of the common later-onset α-galactosidase A IVS4+919G→A mutation in Taiwanese newborns--superiority of DNA-based to enzyme-based newborn screening for common mutations. | Chien YH | Molecular medicine (Cambridge, Mass.) | 2012 | PMID: 22437327 |
Enzyme assay and clinical assessment in subjects with a Chinese hotspot late-onset Fabry mutation (IVS4 + 919G→A). | Lin HY | Journal of inherited metabolic disease | 2010 | PMID: 20821055 |
Transposable elements in disease-associated cryptic exons. | Vorechovsky I | Human genetics | 2010 | PMID: 19823873 |
High incidence of the cardiac variant of Fabry disease revealed by newborn screening in the Taiwan Chinese population. | Lin HY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031620 |
Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). | Hwu WL | Human mutation | 2009 | PMID: 19621417 |
Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype. | Ishii S | American journal of human genetics | 2002 | PMID: 11828341 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f4806ec3-a09b-4c34-87b8-4c34ef3b1113 | - | - | - | - |
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Text-mined citations for rs199473684 ...
HelpRecord last updated May 12, 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.