ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.966C>A (p.Asp322Glu)
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.966C>A (p.Asp322Glu)
Variation ID: 222459 Accession: VCV000222459.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398403 (GRCh38) [ NCBI UCSC ] X: 100653391 (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 Dec 15, 2018 Feb 14, 2024 Oct 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.966C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Asp322Glu missense NM_001199973.2:c.300+2946G>T intron variant NM_001199974.2:c.177+6581G>T intron variant NM_001406747.1:c.1089C>A NP_001393676.1:p.Asp363Glu missense NM_001406748.1:c.966C>A NP_001393677.1:p.Asp322Glu missense NR_164783.1:n.1045C>A non-coding transcript variant NR_176252.1:n.896C>A non-coding transcript variant NR_176253.1:n.1103C>A non-coding transcript variant NC_000023.11:g.101398403G>T NC_000023.10:g.100653391G>T NG_007119.1:g.14561C>A LRG_672:g.14561C>A LRG_672t1:c.966C>A LRG_672p1:p.Asp322Glu - Protein change
- D322E, D363E
- Other names
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- Canonical SPDI
- NC_000023.11:101398402:G:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1255 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1289 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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May 3, 2018 | RCV000367678.14 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2023 | RCV000780289.18 |
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
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 03, 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: SCV000331016.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 16
Sex: mixed
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Pathogenic
(Feb 21, 2018)
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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: SCV000917440.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GLA c.966C>A (p.Asp322Glu) 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.966C>A (p.Asp322Glu) 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 87728 control chromosomes. c.966C>A has been reported in the literature in multiple individuals affected with Fabry Disease,including largre family with co-segregation (Adalsteinsdottir_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The leukocyte -GalA activity was less than 10% in all affected male family members reported in Adalsteinsdottir, 2017. In addition, another alteration of the same nucleotide, c.966C>G, leading to the same protein change, p.D322E, was reported in pt presented with classical FD (Lee, 2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified 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: SCV002054391.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Oct 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: SCV001590649.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 322 of the GLA … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 322 of the GLA protein (p.Asp322Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 28798024). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222459). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 28798024). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Fabry disease
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022207.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000169.3:c.966C>A (chrX:101398403) in GLA was detected in 2 heterozygous females and 4 hemizygous males out of 58K WGS Icelanders (MAF= 0,009%). Following imputation … (more)
The variant NM_000169.3:c.966C>A (chrX:101398403) in GLA was detected in 2 heterozygous females and 4 hemizygous males out of 58K WGS Icelanders (MAF= 0,009%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes, 3 imputed hemizygotes) we observed an association with hypertrophic cardiomyopathy (using 640 cases and 355022 controls (OR= 30.02, P= 1.90e-04)) under an additive model. Furthermore, we observed an association with cardiomyopathy (using 1974 cases and 365360 controls (OR= 13.36, P= 1.25e-03)) under a recessive model. This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PM2, PP5) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 5
Ethnicity/Population group: Icelandic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes. | Adalsteinsdottir B | Circulation. Cardiovascular genetics | 2017 | PMID: 28798024 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs398123226 ...
HelpRecord 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.