ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)
Variation ID: 198401 Accession: VCV000198401.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398012 (GRCh38) [ NCBI UCSC ] X: 100653000 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 29, 2015 Feb 14, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.1087C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Arg363Cys missense NM_000169.2(GLA):c.1087C>T NM_001199973.2:c.300+2555G>A intron variant NM_001199974.2:c.177+6190G>A intron variant NR_164783.1:n.1166C>T non-coding transcript variant NC_000023.11:g.101398012G>A NC_000023.10:g.100653000G>A NG_007119.1:g.14952C>T LRG_672:g.14952C>T LRG_672t1:c.1087C>T LRG_672p1:p.Arg363Cys - Protein change
- R363C
- Other names
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- Canonical SPDI
- NC_000023.11:101398011:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1239 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1270 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000179729.10 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV001249019.17 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 03, 2015)
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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: SCV000232023.5
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 5
Sex: mixed
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Likely pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054374.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Likely pathogenic
(Jul 01, 2022)
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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: SCV001554529.2
First in ClinVar: Apr 13, 2021 Last updated: Sep 17, 2022 |
Comment:
Variant summary: GLA c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded … (more)
Variant summary: GLA c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183376 control chromosomes (gnomAD). c.1087C>T has been reported in the literature in individuals affected with later onset or non-classic presentations of Fabry Disease (example, Balendran_2020, Mauhin_2020, Arends_2018) and as a variant causing classical Fabry disease (example, Shabbeer_2002, cited in Benjamin_2009). These data do not allow a firm conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (example, Wu_2011, Benjamin_2009). The most pronounced variant effect results in <10% of normal activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 13, 2023)
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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: SCV003194980.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Published functional studies demonstrate significantly reduced enzyme activity (Wu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on … (more)
Published functional studies demonstrate significantly reduced enzyme activity (Wu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29437868, 31860127, 25382311, 22063097, 28615118, 12175777, 27657681, 32442237, 31987665, 21598360) (less)
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Pathogenic
(Aug 15, 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: SCV002024322.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jul 09, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001736310.2
First in ClinVar: Jun 19, 2021 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces arginine with cysteine at codon 363 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 363 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to 7.5% residual GLA enzyme activity when expressed in HEK-293 cells (PMID: 21598360). This variant has been reported in individuals affected with Fabry disease (PMID: 12175777, 19387866, 28749998, 29661900, 32442237) and a female with left ventricular hypertrophy (PMID: 31987665). Cultured cells from an affected male showed 8% residual GLA enzyme activity (PMID: 19387866), and an affected female showed elevated lysoglobotriaosylceramide levels (PMID: 28749998). This variant has been reported in a newborn (PMID: 28615118) and in a 33-year-old asymptomatic female (PMID: 31117083). Both of them had reduced GLA enzyme activity. This variant has been identified in 2/183376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg363His, has been associated with Fabry disease (Clinvar variation ID: 222141), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(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: SCV001422923.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Arg363Cys variant in GLA has been reported in the literature in two males with classic Fabry, as well as in five individuals in ClinVar … (more)
The p.Arg363Cys variant in GLA has been reported in the literature in two males with classic Fabry, as well as in five individuals in ClinVar (PMID: 12175777, 21598360; ID:198401), and has been identified in 0.00244% (2/81841) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044776). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as pathogenic by EGL Genetic Diagnostics (VariationID:198401). In vitro functional studies provide some evidence that the p.Arg363Cys variant may slightly impact protein function (PMID: 21598360, 27744182, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype that is consistent with disease (PMID: 12175777). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Arg363His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 28302345,12175777, 23935525, 26937405,11668641,25382311/Variation ID: 222141). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PS4_moderate, PP4, PM5_supporting (Richards 2015). (less)
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Likely pathogenic
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807958.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 19, 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: SCV001575313.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the GLA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the GLA protein (p.Arg363Cys). This variant is present in population databases (rs797044776, gnomAD 0.002%). This missense change has been observed in individual(s) with features of Fabry disease (PMID: 12175777; Invitae). ClinVar contains an entry for this variant (Variation ID: 198401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668641, 12175777, 26937405, 28302345). 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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Likely pathogenic
(Jun 27, 2019)
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no assertion criteria provided
Method: research
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Fabry disease
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430847.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
GLA Arg353Cys has been previously identified in 5 Fabry patients (Phyu P, et al., 2018; Pettazzoni M, et al., 2017; Benjamin ER, et al., 2009; … (more)
GLA Arg353Cys has been previously identified in 5 Fabry patients (Phyu P, et al., 2018; Pettazzoni M, et al., 2017; Benjamin ER, et al., 2009; Shabbeer J, et al., 2002). We identified this variant in a patient presenting with left ventricular hypertrophy, subsequent clinical screening confirmed a diagnosis of Fabry disease. The variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.000011 http://gnomad.broadinstitute.org/). In silico tools SIFT and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "Disease causing". Interestingly another amino acid change at this position (Arg363His) has been classified as pathogenic. suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on rarity in the general population, reports of this variant in affected individuals, and because Fabry disease is caused only by variants in the GLA gene, we classify GLA Arg353Cys as "likely pathogenic". (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Cornea verticillata and acroparesthesia efficiently discriminate clusters of severity in Fabry disease. | Mauhin W | PloS one | 2020 | PMID: 32442237 |
Diagnostic strategy for females suspected of Fabry disease. | Balendran S | Clinical genetics | 2020 | PMID: 31860127 |
Genomic screening of Fabry disease in young stroke patients: the Taiwan experience and a review of the literature. | Lee TH | European journal of neurology | 2019 | PMID: 30103270 |
Increased resting cerebral blood flow in adult Fabry disease: MRI arterial spin labeling study. | Phyu P | Neurology | 2018 | PMID: 29661900 |
Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. | Arends M | Journal of medical genetics | 2018 | PMID: 29437868 |
Functional and biological studies of α-galactosidase A variants with uncertain significance from newborn screening in Taiwan. | Liao HC | Molecular genetics and metabolism | 2018 | PMID: 28615118 |
LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. | Pettazzoni M | PloS one | 2017 | PMID: 28749998 |
Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system. | Navarrete-Martínez JI | Molecular genetics and metabolism | 2017 | PMID: 28302345 |
The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations. | Citro V | International journal of molecular sciences | 2016 | PMID: 27916943 |
Late onset variants in Fabry disease: Results in high risk population screenings in Argentina. | Serebrinsky G | Molecular genetics and metabolism reports | 2015 | PMID: 26937405 |
Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS). | Liu HC | JIMD reports | 2015 | PMID: 25762495 |
The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots. | Tai CL | Clinica chimica acta; international journal of clinical chemistry | 2012 | PMID: 22063097 |
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 the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study. | Andreotti G | Orphanet journal of rare diseases | 2010 | PMID: 21138548 |
The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines. | Benjamin ER | Journal of inherited metabolic disease | 2009 | PMID: 19387866 |
Fabry disease: correlation between structural changes in alpha-galactosidase, and clinical and biochemical phenotypes. | Matsuzawa F | Human genetics | 2005 | PMID: 15924232 |
The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. | Garman SC | Journal of molecular biology | 2004 | PMID: 15003450 |
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. | Shabbeer J | Molecular genetics and metabolism | 2002 | PMID: 12175777 |
Fabry disease: 20 novel GLA mutations in 35 families. | Blaydon D | Human mutation | 2001 | PMID: 11668641 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7415da6b-e88c-485b-8fb1-a633f31bfcfa | - | - | - | - |
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Text-mined citations for rs797044776 ...
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.