Variant summary: GLA c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182951 control chromosomes (gnomAD). c.1024C>T has been reported in the literature in individuals affected with Fabry Disease (Davies_1993, Lee_2010, Uribe_2015, Rigoldi_2014). These data indicate that the variant is likely to be associated with disease. Patients carrying the variant of interest were found to have 0% GLA activity (Lee_2010, Uribe_2015). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites 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.1024C>T (p.Arg342Ter)
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
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NM_000169.3(GLA):c.1024C>T (p.Arg342Ter)
Variation ID: 10743 Accession: VCV000010743.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398075 (GRCh38) [ NCBI UCSC ] X: 100653063 (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 Feb 14, 2024 Jul 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.1024C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Arg342Ter nonsense NM_001199973.2:c.300+2618G>A intron variant NM_001199974.2:c.177+6253G>A intron variant NM_001406747.1:c.1147C>T NP_001393676.1:p.Arg383Ter nonsense NR_164783.1:n.1103C>T non-coding transcript variant NR_176252.1:n.954C>T non-coding transcript variant NR_176253.1:n.1161C>T non-coding transcript variant NC_000023.11:g.101398075G>A NC_000023.10:g.100653063G>A NG_007119.1:g.14889C>T LRG_672:g.14889C>T LRG_672t1:c.1024C>T LRG_672p1:p.Arg342Ter - Protein change
- R342*, R383*
- Other names
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NP_000160.1:p.Arg342*
- Canonical SPDI
- NC_000023.11:101398074: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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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.
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- 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
|
Jul 13, 2023 | RCV000011491.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2023 | RCV000723730.12 | |
|
GLA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV003398484.4 |
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
(May 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363732.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GLA c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GLA c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182951 control chromosomes (gnomAD). c.1024C>T has been reported in the literature in individuals affected with Fabry Disease (Davies_1993, Lee_2010, Uribe_2015, Rigoldi_2014). These data indicate that the variant is likely to be associated with disease. Patients carrying the variant of interest were found to have 0% GLA activity (Lee_2010, Uribe_2015). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites 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)
|
criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054382.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Jan 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GLA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004111846.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GLA c.1024C>T variant is predicted to result in premature protein termination (p.Arg342*). This variant has been reported in multiple individuals with classic Fabry disease … (more)
The GLA c.1024C>T variant is predicted to result in premature protein termination (p.Arg342*). This variant has been reported in multiple individuals with classic Fabry disease (Davies et al. 1993. PubMed ID: 8395937; Park et al. 2009. PubMed ID: 19287194; Rigoldi et al. 2013. PubMed ID: 23980562; Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). In patients with this variant the GLA activity in leukocytes was shown to be 0% of the normal GLA enzymatic activity (Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLA gene are expected to be pathogenic. Although this variant occurs in the last exon and may not result in nonsense mediated decay, other pathogenic variants were reported downstream of this variant. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 06, 2019)
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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: SCV002024296.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jun 28, 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: SCV000110101.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 11
Sex: mixed
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Pathogenic
(Dec 10, 2018)
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criteria provided, single submitter
Method: research
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993561.1 First in ClinVar: Sep 25, 2019 Last updated: Sep 25, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 24, 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: SCV003798845.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28579207, 23980562, 19287194, 8395937, 16595074, 20505683, 11668641, 28723748, 27156739, 11076046, 26297554) (less)
|
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Pathogenic
(Jul 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000283689.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 10743). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 8395937, … (more)
ClinVar contains an entry for this variant (Variation ID: 10743). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 8395937, 16595074, 19287194, 20505683, 23980562, 26297554). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg342*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the GLA protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GLA function (PMID: 20505683). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 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
|
OMIM
Accession: SCV000031723.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a Greek/English patient with classic Fabry disease (301500), Davies et al. (1993) found a CGA-to-TGA mutation in exon 7 of the GLA gene, resulting … (more)
In a Greek/English patient with classic Fabry disease (301500), Davies et al. (1993) found a CGA-to-TGA mutation in exon 7 of the GLA gene, resulting in an arg342-to-ter (R342X) substitution. (less)
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
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Fabry disease
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749933.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 02-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 02-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal retinal morphology (present) , Stroke disorder (present) , Obesity (present) , Hyperthyroidism (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-02-05
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
The GLA c.1024C>T variant is predicted to result in premature protein termination (p.Arg342*). This variant has been reported in multiple individuals with classic Fabry disease (Davies et al. 1993. PubMed ID: 8395937; Park et al. 2009. PubMed ID: 19287194; Rigoldi et al. 2013. PubMed ID: 23980562; Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). In patients with this variant the GLA activity in leukocytes was shown to be 0% of the normal GLA enzymatic activity (Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLA gene are expected to be pathogenic. Although this variant occurs in the last exon and may not result in nonsense mediated decay, other pathogenic variants were reported downstream of this variant. This variant is interpreted as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28579207, 23980562, 19287194, 8395937, 16595074, 20505683, 11668641, 28723748, 27156739, 11076046, 26297554)
Comment:
ClinVar contains an entry for this variant (Variation ID: 10743). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 8395937, 16595074, 19287194, 20505683, 23980562, 26297554). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg342*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the GLA protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GLA function (PMID: 20505683). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 02-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182951 control chromosomes (gnomAD). c.1024C>T has been reported in the literature in individuals affected with Fabry Disease (Davies_1993, Lee_2010, Uribe_2015, Rigoldi_2014). These data indicate that the variant is likely to be associated with disease. Patients carrying the variant of interest were found to have 0% GLA activity (Lee_2010, Uribe_2015). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The GLA c.1024C>T variant is predicted to result in premature protein termination (p.Arg342*). This variant has been reported in multiple individuals with classic Fabry disease (Davies et al. 1993. PubMed ID: 8395937; Park et al. 2009. PubMed ID: 19287194; Rigoldi et al. 2013. PubMed ID: 23980562; Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). In patients with this variant the GLA activity in leukocytes was shown to be 0% of the normal GLA enzymatic activity (Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLA gene are expected to be pathogenic. Although this variant occurs in the last exon and may not result in nonsense mediated decay, other pathogenic variants were reported downstream of this variant. This variant is interpreted as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28579207, 23980562, 19287194, 8395937, 16595074, 20505683, 11668641, 28723748, 27156739, 11076046, 26297554)
Comment:
ClinVar contains an entry for this variant (Variation ID: 10743). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 8395937, 16595074, 19287194, 20505683, 23980562, 26297554). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg342*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the GLA protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GLA function (PMID: 20505683). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 02-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of mutations in Colombian patients affected with Fabry disease. | Uribe A | Gene | 2015 | PMID: 26297554 |
| Intrafamilial phenotypic variability in four families with Anderson-Fabry disease. | Rigoldi M | Clinical genetics | 2014 | PMID: 23980562 |
| Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. | Lee BH | Journal of human genetics | 2010 | PMID: 20505683 |
| Effects of a chemical chaperone on genetic mutations in alpha-galactosidase A in Korean patients with Fabry disease. | Park JY | Experimental & molecular medicine | 2009 | PMID: 19287194 |
| Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. | Shabbeer J | Human genomics | 2006 | PMID: 16595074 |
| Mutation analysis in patients with the typical form of Anderson-Fabry disease. | Davies JP | Human molecular genetics | 1993 | PMID: 8395937 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs104894843 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.