ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.644A>G (p.Asn215Ser)
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.644A>G (p.Asn215Ser)
Variation ID: 10730 Accession: VCV000010730.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398942 (GRCh38) [ NCBI UCSC ] X: 100653930 (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 Apr 4, 2013 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.644A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Asn215Ser missense NM_001199973.2:c.300+3485T>C intron variant NM_001199974.2:c.177+7120T>C intron variant NR_164783.1:n.723A>G non-coding transcript variant NC_000023.11:g.101398942T>C NC_000023.10:g.100653930T>C NG_007119.1:g.14022A>G LRG_672:g.14022A>G LRG_672t1:c.644A>G P06280:p.Asn215Ser - Protein change
- N215S
- Other names
- p.N215S:AAT>AGT
- Canonical SPDI
- NC_000023.11:101398941:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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 |
6 | 1239 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1269 |
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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Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000011477.41 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Oct 16, 2023 | RCV000157896.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV000618059.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2014 | RCV000844705.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2021 | RCV001798000.11 |
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 22, 2018)
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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: SCV000110129.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 78
Sex: mixed
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Pathogenic
(Mar 05, 2019)
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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: SCV000928264.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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Pathogenic
(Apr 02, 2014)
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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: SCV000198194.4
First in ClinVar: Jan 30, 2015 Last updated: Dec 06, 2016 |
Comment:
The p.Asn215Ser variant in GLA has been reported in >20 individuals, both male a nd female, with a clinical diagnosis of HCM and/or cardiac Fabry … (more)
The p.Asn215Ser variant in GLA has been reported in >20 individuals, both male a nd female, with a clinical diagnosis of HCM and/or cardiac Fabry disease, and at least one male with features of classic Fabry disease (Davies 1993, Eng 1994, T opalaglu 1999, Walsh 2017, Oder 2017, LMM unpublished data). This variant has be en identified in 1/80091 of European chromosomes by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). Multiple funct ional studies have shown that the p.Asn215Ser variant protein has reduced enzyma tic activity (Mills 2005, Ishii 2007, Wu 2011, Ebrahim 2012, Tian 2013). This va riant has also been reported in ClinVar (Variation ID#10730). In summary, this v ariant meets criteria to be classified as pathogenic for hypertrophic cardiomyop athy based upon presence in probands, very low frequency in controls, and functi onal evidence. ACMG criteria applied: PS3, PM2, PS4 (less)
Number of individuals with the variant: 7
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Pathogenic
(Apr 08, 2019)
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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: SCV000917441.2
First in ClinVar: May 31, 2019 Last updated: Nov 08, 2019 |
Comment:
Variant summary: GLA c.644A>G (p.Asn215Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.644A>G (p.Asn215Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 178708 control chromosomes (gnomAD). c.644A>G has been reported in the literature in multiple individuals affected with Fabry Disease. The variant has been identified in numerous patients and families with Fabry disease and is considered a known recurrent mutation that is associated with later-onset disease. A recent multi-center study of 125 Fabry disease patients with this mutation reported their study "confirms that p.N215S is a disease-causing Fabry mutation with severe clinical manifestations essentially limited to the heart until late adulthood, especially in males."(Germain_2018) Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV002054425.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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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: SCV001422796.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Asn215Ser variant in GLA has been reported in at least 15 individuals from the literature with Fabry Disease (PMID:21598360, 10666480, 26047621, 23935525, 29621274), segregated … (more)
The p.Asn215Ser variant in GLA has been reported in at least 15 individuals from the literature with Fabry Disease (PMID:21598360, 10666480, 26047621, 23935525, 29621274), segregated with disease in 6 affected relatives from 1 family (PMID: 23818648), and has been identified in 0.001221% (1/81881) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). 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 multiple sources including Eurofins Clinical Diagnostics, Ambry Genetics, Fulgent Genetics, GeneDx, Invitae, Laboratory for Molecular Medicine (Partners Healthcare), Mayo Clinic, and OMIM (VariationID:10730). In vitro functional studies provide evidence of decreased enzymatic activity and protein stability, and therefore the p.Asn215Ser variant may impact protein function (PMID: 23935525, 23568732, 21972175, 21598360, 17555407,15702404, 16773563). 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: 30023289, 29621274,15895718, 7504405, 27532257, 26047621, 23935525, 15702404, 10666480, 7911050, 15091117, 11914245, 11531969, 18849176, 15712228, 21062768, 16773563, 23568732, 8395937). In summary, this variant meets criteria to be classified as pathogenic for Fabry disease based on multiple reports in the literature and ClinVar, reduced enzymatic activity in functional studies, low frequency in the general populaiton, and computational and conservation data. ACMG/AMP Criteria applied: PP4_moderate, PS3_Moderate, PS4, PP3, PP1, PM2_supporting (Richards 2015). (less)
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: research
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Fabry disease
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, University of Torino
Study: NeuroWES
Accession: SCV002760136.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(Aug 18, 2021)
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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
Accession: SCV002042026.2
First in ClinVar: Jan 03, 2022 Last updated: Mar 11, 2023 |
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Pathogenic
(Jul 13, 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: SCV002024818.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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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
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004357520.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment … (more)
This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites; glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations (left ventricular hypertrophy, arrhythmia) in later adulthood (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, 37205992, 37480128, 38002959). This variant has also been reported in individuals affected with classic Fabry disease or renal impairment, but less frequently (PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 29, 2023)
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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: SCV000739938.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.N215S pathogenic mutation (also known as c.644A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at … (more)
The p.N215S pathogenic mutation (also known as c.644A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at nucleotide position 644. The asparagine at codon 215 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in patients with Fabry disease, hypertrophic cardiomyopathy (HCM), and renal disease (Davies JP et al. Hum Mol Genet. 1993;2(7):1051-3; Eng CM et al. Am J Hum Genet. 1993;53(6):1186-97; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Pasqualim G et al. Clin. Biochem., 2014 May;47:657-62; Militaru S et al. Curr Health Sci J Oct;45:272-277; Sheng B et al. Mol Genet Metab Rep, 2020 Sep;24:100596; Tian ML et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013 Apr;30:185-8; Duro G et al. Int J Mol Sci, 2018 Nov;19; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Koulousios K et al. BMJ Open, 2017 Oct;7:e017098; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). This variant has also been observed to co-segregate with Fabry disease in multiple families (Tomberli B et al. Eur J Heart Fail. 2013;15(12):1363-73; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Spada M et al. Am J Hum Genet. 2006;79(1):31-40). It has been reported in the heterozygous state in a woman with Fabry disease and progressive cardiac dysfunction, who also had another heterozygous variant in GLA (p.C202R, c.604T>C) (McConnell EJ et al. Eur Heart J Case Rep, 2018 Dec;2:yty122). Individuals with this alteration have been reported to have later age of onset and fewer extracardiac findings when compared to individuals with classic Fabry disease (Thomas A et al. Molec Gen and Metab. 2015 Feb;114(2):S113; Frustaci A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:799-805; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Lavalle L et al. PLoS ONE, 2018 Apr;13:e0193550; Oder D et al. Circ Cardiovasc Genet, 2017 Oct;10; Germain DP et al. Mol Genet Genomic Med, 2018 Apr). In several functional in vitro analyses, this alteration has demonstrated a reduction in alpha-galactosidase A enzyme activity, suggesting variable expressivity among clinical phenotypes depending on residual enzyme activity (Spada M et al. Am J Hum Genet. 2006;79(1):31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Ebrahim HY et al. J. Inherit. Metab. Dis., 2012 Mar;35:325-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Fabry disease
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768160.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0103 - Loss of function and dominant negative … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0103 - Loss of function and dominant negative are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Loss of function is a known mechanism of disease in males. Females can be affected but with variable severity unexplained by skewed X-inactivation (PMID: 31613176), suggested to be due to the dominant negative mechanism of some variants. Truncating variants in the last exon have been reported with a dominant negative mechanism in females. Gain of function has also been suggested; however more evidence is required (PMIDs: 8878432; 31613176). (I) 0109 - This gene is associated with X-linked disease. Both males and females have been reported with Fabry disease, though the latter are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a condition (0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated melibiase_2 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent mutation associated with late-onset Fabry disease (ClinVar, PMIDs: 32435590; 29018006). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 14, 2022)
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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: SCV000611200.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 02, 2022)
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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: SCV000207827.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
One of the most common later-onset Fabry disease GLA variants reported in individuals of European or North American descent, with cardiac manifestations as the typical … (more)
One of the most common later-onset Fabry disease GLA variants reported in individuals of European or North American descent, with cardiac manifestations as the typical presenting feature (Davies et al., 1993; Mills et al., 2005; Spada et al., 2006; Oder et al., 2017; Germain et al., 2018; Sheng et al., 2020); Published functional studies demonstrate a damaging effect as this variant is associated with reduced alpha-galactosidase A enzyme activity compared to wild-type (Spada et al. 2006; 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: 21972175, 25382311, 28943383, 31020198, 28793143, 15702404, 23568732, 17555407, 23935525, 25611685, 26047621, 27532257, 28728877, 27657681, 28988177, 24582695, 28649509, 31308319, 31956509, 30477121, 31447099, 32150461, 33673806, 32686758, 16773563, 21062768, 15886492, 31393666, 29649853, 29018006, 29621274, 8395937, 32435590, 30023289, 21598360) (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239093.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 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: SCV000543776.9
First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 215 of the GLA protein (p.Asn215Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 215 of the GLA protein (p.Asn215Ser). This variant is present in population databases (rs28935197, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of Fabry disease (PMID: 8395937, 11531969, 11914245, 15091117, 15702404, 15712228, 18849176). ClinVar contains an entry for this variant (Variation ID: 10730). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 21598360). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563354.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The GLA c.644A>G; p.Asn215Ser variant (rs28935197) is reported in the literature in numerous individuals and families affected with Fabry disease, typically with later onset and … (more)
The GLA c.644A>G; p.Asn215Ser variant (rs28935197) is reported in the literature in numerous individuals and families affected with Fabry disease, typically with later onset and cardiac specific presentation (Eng 1993, Ishii 2007, Lavalle 2018, Oder 2017, Spada 2006, Tomberli 2013). Functional analyses demonstrate that enzyme with this variant has reduced stability/activity (Ishii 2007, Spada 2006). This variant is also reported in ClinVar (Variation ID: 10730). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.72). Based on available information, this variant is considered to be pathogenic. References: Eng CM et al. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PMID: 7504405. Ishii S et al. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 2007 Sep 1;406(2):285-95. PMID: 17555407. Lavalle L et al. Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS One. 2018 Apr 5;13(4):e0193550. PMID: 29621274. Oder D et al. alpha-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease. Circ Cardiovasc Genet. 2017 Oct;10(5):e001691. PMID: 29018006. Spada M et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40. PMID: 16773563. Tomberli B et al. Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. Eur J Heart Fail. 2013 Dec;15(12):1363-73. PMID: 23818648. (less)
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Pathogenic
(Jan 06, 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
|
All of Us Research Program, National Institutes of Health
Accession: SCV004821932.1
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 missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment … (more)
This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites and glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations in late adulthood, especially in males (e.g. left ventricular hypertrophy, arrhythmia) (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, etc.). Cases with classic Fabry disease or renal impairment have also been reported but less frequently (e.g. PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 3
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Pathogenic
(Feb 27, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000800936.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Dec 01, 1993)
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no assertion criteria provided
Method: literature only
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FABRY DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031709.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Eng et al. (1993) and Davies et al. (1993) described an A-to-G transition in exon 5 of the GLA gene, resulting in an asn215-to-ser (N215S) … (more)
Eng et al. (1993) and Davies et al. (1993) described an A-to-G transition in exon 5 of the GLA gene, resulting in an asn215-to-ser (N215S) substitution. The patients had mild forms of Fabry disease (301500) and residual enzyme activity. (less)
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Pathogenic
(Jun 06, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925088.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
Given the strong case data and functional studies demonstrating impaired alpha-galactosidase enzyme activity we consider this variant to be disease-causing and we do feel it … (more)
Given the strong case data and functional studies demonstrating impaired alpha-galactosidase enzyme activity we consider this variant to be disease-causing and we do feel it is suitable for establishing a diagnosis/carrier status of Fabry disease and assessing risk in healthy relatives ("predictive genetic testing"). There is strong case data for this variant, which has been reported in >9 unrelated cases of Fabry disease (not including this patient's family). We have seen the variant in a case of hypertrophic cardiomyopathy. Testing was done at Invitae. The variant has been reported in cases of "variant" phenotypes of Fabry disease, such as cases with isolated cardiac or renal disease, but has also been reported in classic cases. Please note that given the robust case data, the literature review performed in this case was not comprehensive. Eng et al., 1993 from the Desnick group at Mount Sinai reported the Arg215Ser variant in 3 unrelated people with isolated cardiac involvement including left ventricular hypertrophy. Davies et al., 1993 reported the Arg215Ser variant in a patient with classic Fabry disease. Altarescu et al., 2001 reported the Arg215Ser variant in 4 patients from 3 families with signs of Fabry disease, two of whom had angiokeratomas and mucosal anhydrosis (related) and one of whom had a cardiac phenotype (unrelated). All were reported to have alpha-galactosidase A activity of <11% of controls. One compound heterozygous female had a renal phenotype and was noted to have 0.7% alpha-Gal A activity. Sachdev et al., 2002 reported 3 males with the Arg215Ser variant and low alpha-Gal A activity in a study screening men with HCM for Fabry disease. It was not clear whether they may have been related or not or if they had a pure cardiac phenotype or other manifestations. Shabeer et al., 2005 reported the Arg215Ser variant in a female. No specific case data was provided; however, it was noted that the females tested were from Fabry families with unknown variants or clinically suspected to be affected. Erdos et al., 2008 reported the Arg215Ser variant in a Hungarian family with Fabry disease. It was identified in 3 males and 6 females; specific segregation data was not provided. One of the females had severe renal disease with proteinuria diagnosed at 25 and was found to be homozygous for the variant as a result of consanguinity. She and two other family members were noted to not have cardiac involvement. This mutation affects a highly conserved, functional N-glycosylation consensus site of the enzyme, but the expressed enzyme retains some activity. This is consistent with clinical observations of some families with variant presentations confined to one organ system. There is no variation at codon 215 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). The mean coverage at that site in ExAC is 80x with median coverage of 90x and over 95% of individuals with 30x coverage. (less)
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Pathogenic
(Sep 16, 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: SCV001457723.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Genotype-Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants. | Savostyanov K | Genes | 2023 | PMID: 38002959 |
Low skeletal muscle mass as an early sign in children with fabry disease. | Lu Z | Orphanet journal of rare diseases | 2023 | PMID: 37480128 |
Early onset of nephrogenic diabetes insipidus due to fabry disease in a child with GLA N215S mutation: Case report and literature review. | Lu Z | Heliyon | 2023 | PMID: 37205992 |
Nationwide screening of Fabry disease in patients with hypertrophic cardiomyopathy in Czech Republic. | Zemánek D | ESC heart failure | 2022 | PMID: 36087038 |
Relapsing minimal change disease superimposed on late-onset p.N215S Fabry nephropathy. | Salerno FR | Clinical kidney journal | 2021 | PMID: 35035949 |
Globotrioasylsphingosine Levels and Optical Coherence Tomography Angiography in Fabry Disease Patients. | Wiest MRJ | Journal of clinical medicine | 2021 | PMID: 33807900 |
Globotriaosylsphingosine (lyso-Gb(3)) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort. | Effraimidis G | Journal of medical genetics | 2021 | PMID: 32963035 |
Mono-symptomatic Fabry disease in a population with mild-to-moderate left ventricular hypertrophy. | Fuller M | Molecular genetics and metabolism reports | 2020 | PMID: 33335842 |
Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy. | Sheng B | Molecular genetics and metabolism reports | 2020 | PMID: 32435590 |
Prognostic significance of right ventricular hypertrophy and systolic function in Anderson-Fabry disease. | Graziani F | ESC heart failure | 2020 | PMID: 32432376 |
Genetic Testing for Diagnosis of Hypertrophic Cardiomyopathy Mimics: Yield and Clinical Significance. | Hoss S | Circulation. Genomic and precision medicine | 2020 | PMID: 32150461 |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients. | Varela P | Orphanet journal of rare diseases | 2020 | PMID: 31996269 |
Translational readthrough of GLA nonsense mutations suggests dominant-negative effects exerted by the interaction of wild-type and missense variants. | Lombardi S | RNA biology | 2020 | PMID: 31613176 |
Demographic and Clinical Characteristics of the Full 2015-2018 Cohort of Romanian Fabry Disease Patients. | Militaru S | Current health sciences journal | 2019 | PMID: 32042454 |
Progressive cardiac involvement in a compound heterozygote Fabry patient: a case report. | McConnell EJ | European heart journal. Case reports | 2018 | PMID: 31020198 |
Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? | Duro G | International journal of molecular sciences | 2018 | PMID: 30477121 |
Fabry disease in a Japanese population-molecular and biochemical characteristics. | Sakuraba H | Molecular genetics and metabolism reports | 2018 | PMID: 30386727 |
An atypical p.N215S variant of Fabry disease with end-stage renal failure. | Sugarman M | Molecular genetics and metabolism reports | 2018 | PMID: 30023289 |
Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study. | Germain DP | Molecular genetics & genomic medicine | 2018 | PMID: 29649853 |
Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. | Lavalle L | PloS one | 2018 | PMID: 29621274 |
Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy. | Maron MS | The American journal of medicine | 2018 | PMID: 28943383 |
α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease. | Oder D | Circulation. Cardiovascular genetics | 2017 | PMID: 29018006 |
Fabry disease due to D313Y and novel GLA mutations. | Koulousios K | BMJ open | 2017 | PMID: 28988177 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype-phenotype expression. | Paliouras C | Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia | 2015 | PMID: 26384850 |
Pathology and function of conduction tissue in Fabry disease cardiomyopathy. | Frustaci A | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26047621 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
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 |
Fabry disease: a new approach for the screening of females in high-risk groups. | Pasqualim G | Clinical biochemistry | 2014 | PMID: 24582695 |
Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease. | Lukas J | PLoS genetics | 2013 | PMID: 23935525 |
Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. | Tomberli B | European journal of heart failure | 2013 | PMID: 23818648 |
[Genetic and clinical study of three Chinese pedigrees with Fabry disease]. | Tian ML | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2013 | PMID: 23568732 |
Vascular endothelial growth factor (VEGF-a) in Fabry disease: association with cutaneous and systemic manifestations with vascular involvement. | Zampetti A | Cytokine | 2013 | PMID: 23332617 |
Functional analysis of variant lysosomal acid glycosidases of Anderson-Fabry and Pompe disease in a human embryonic kidney epithelial cell line (HEK 293 T). | Ebrahim HY | Journal of inherited metabolic disease | 2012 | PMID: 21972175 |
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 |
Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study. | Hagège AA | Heart (British Cardiac Society) | 2011 | PMID: 21062768 |
Novel sequence variants of the alpha-galactosidase A gene in patients with Fabry disease. | Erdos M | Molecular genetics and metabolism | 2008 | PMID: 18849176 |
Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. | Ishii S | The Biochemical journal | 2007 | PMID: 17555407 |
High incidence of later-onset fabry disease revealed by newborn screening. | Spada M | American journal of human genetics | 2006 | PMID: 16773563 |
Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. | Shabbeer J | Human mutation | 2005 | PMID: 15712228 |
Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease. | Mills K | Journal of inherited metabolic disease | 2005 | PMID: 15702404 |
Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. | Glass RB | Journal of computer assisted tomography | 2004 | PMID: 15091117 |
The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. | Garman SC | Journal of molecular biology | 2004 | PMID: 15003450 |
Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. | Sachdev B | Circulation | 2002 | PMID: 11914245 |
Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease. | Altarescu GM | Clinical genetics | 2001 | PMID: 11531969 |
Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. | Topaloglu AK | Molecular medicine (Cambridge, Mass.) | 1999 | PMID: 10666480 |
Human alpha-galactosidase A: glycosylation site 3 is essential for enzyme solubility. | Ioannou YA | The Biochemical journal | 1998 | PMID: 9620884 |
A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain. Increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. | Miyamura N | The Journal of clinical investigation | 1996 | PMID: 8878432 |
Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. | Eng CM | Human mutation | 1994 | PMID: 7911050 |
Mutation analysis in patients with the typical form of Anderson-Fabry disease. | Davies JP | Human molecular genetics | 1993 | PMID: 8395937 |
Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. | Eng CM | American journal of human genetics | 1993 | PMID: 7504405 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/13f234f0-6aac-4fb9-a162-003e80aacd07 | - | - | - | - |
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Text-mined citations for rs28935197 ...
HelpRecord last updated Jun 02, 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.