Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.680G>A (p.Arg227Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000169.3(GLA):c.680G>A (p.Arg227Gln)
Variation ID: 10732 Accession: VCV000010732.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq22.1 X: 101398906 (GRCh38) [ NCBI UCSC ] X: 100653894 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Sep 16, 2024 Aug 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.680G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Arg227Gln missense NM_001199973.2:c.300+3449C>T intron variant NM_001199974.2:c.177+7084C>T intron variant NM_001406747.1:c.803G>A NP_001393676.1:p.Arg268Gln missense NM_001406748.1:c.680G>A NP_001393677.1:p.Arg227Gln missense NR_164783.1:n.759G>A non-coding transcript variant NR_176252.1:n.610G>A non-coding transcript variant NR_176253.1:n.817G>A non-coding transcript variant NC_000023.11:g.101398906C>T NC_000023.10:g.100653894C>T NG_007119.1:g.14058G>A LRG_672:g.14058G>A LRG_672t1:c.680G>A LRG_672p1:p.Arg227Gln P06280:p.Arg227Gln - Protein change
- R268Q
- Other names
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R227Q
p.R227Q:CGA>CAA
- Canonical SPDI
- NC_000023.11:101398905:C:T
-
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]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7 | 1257 | |
| RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1295 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 20, 2024 | RCV000011478.40 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 13, 2024 | RCV000157898.21 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695744.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 07, 2020 |
Comment:
Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967592.2
First in ClinVar: Aug 26, 2019 Last updated: Apr 20, 2024 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
|
|
|
Pathogenic
(Jan 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110134.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
|
|
|
Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054418.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013711.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Pain (present) , Cornea verticillata (present)
|
|
|
Pathogenic
(Feb 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226708.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM2, PS3, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024300.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834471.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000207829.7
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); … (more)
The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525) (less)
|
|
|
Pathogenic
(Dec 01, 1993)
|
no assertion criteria provided
Method: literature only
|
FABRY DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031710.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with classic Fabry disease (301500), Eng et al. (1993) described an G-to-A transition in exon 5 of the GLA gene, resulting in … (more)
In a patient with classic Fabry disease (301500), Eng et al. (1993) described an G-to-A transition in exon 5 of the GLA gene, resulting in an arg227-to-gln (R227Q) substitution. This mutation conforms to the CG-to-TG mutation 'hotspot' rule. In the complementary, antisense strand, 5-prime--xxxCGAxxx--3-prime is read as 3-prime--xxxGCTxxx--5-prime. Methylation of the cytosine in the CpG of the antisense codon with subsequent deamidation converts the antisense codon to GTT, which corresponds to the sense codon CAA. Read 5-prime to 3-prime, the CG in the sense strand has been changed to TG in the antisense strand; hence, the designation CG-to-TG 'hotspot' rule. (less)
|
Comment:
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PP3, PP4, PM2, PS3, PS4_moderate
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PP3, PP4, PM2, PS3, PS4_moderate
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy. | Dutra-Clarke M | Molecular genetics and metabolism reports | 2020 | PMID: 33437642 |
| Fabry disease in India: A multicenter study of the clinical and mutation spectrum in 54 patients. | Nampoothiri S | JIMD reports | 2020 | PMID: 33204599 |
| The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. | Benjamin ER | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27657681 |
| Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. | Lukas J | Human mutation | 2016 | PMID: 26415523 |
| Exploratory screening for Fabry's disease in young adults with cerebrovascular disorders in northern Sardinia. | Fancellu L | BMC neurology | 2015 | PMID: 26652600 |
| 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 |
| 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 |
| Ocular manifestations of Fabry disease within in a single kindred. | Morier AM | Optometry (St. Louis, Mo.) | 2010 | PMID: 20615758 |
| 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 |
| Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone. | Shin SH | Pharmacogenetics and genomics | 2008 | PMID: 18698230 |
| The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. | Vedder AC | Journal of inherited metabolic disease | 2007 | PMID: 17206462 |
| Pediatric Fabry disease. | Ries M | Pediatrics | 2005 | PMID: 15713906 |
| Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers. | Morrone A | Journal of medical genetics | 2003 | PMID: 12920095 |
| Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. | Ashton-Prolla P | Journal of investigative medicine : the official publication of the American Federation for Clinical Research | 2000 | PMID: 10916280 |
| 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 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs104894840 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 30, 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.