ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.374A>T (p.His125Leu)
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.374A>T (p.His125Leu)
Variation ID: 1805066 Accession: VCV001805066.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101401805 (GRCh38) [ NCBI UCSC ] X: 100656793 (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 24, 2022 Dec 24, 2022 Feb 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.374A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.His125Leu missense NM_001199973.2:c.300+6348T>A intron variant NM_001199974.2:c.177+9983T>A intron variant NM_001406747.1:c.497A>T NP_001393676.1:p.His166Leu missense NM_001406748.1:c.374A>T NP_001393677.1:p.His125Leu missense NM_001406749.1:c.497A>T NP_001393678.1:p.His166Leu missense NR_164783.1:n.396A>T non-coding transcript variant NR_176252.1:n.396A>T NR_176253.1:n.396A>T NC_000023.11:g.101401805T>A NC_000023.10:g.100656793T>A NG_007119.1:g.11159A>T LRG_672:g.11159A>T LRG_672t1:c.374A>T LRG_672p1:p.His125Leu - Protein change
- H125L, H166L
- Other names
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- Canonical SPDI
- NC_000023.11:101401804:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 | 1217 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1245 |
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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Feb 2, 2022 | RCV002471484.2 |
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
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768194.1
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 a Pathogenic. 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 a Pathogenic. 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 (PMID: 8878432; PMID: 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 histidine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Alpha galactosidase A domain (NCBI). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes with a proline and a tyrosine has each been reported in a male individual with Fabry disease (PMID: 18023222, 27560961). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three male patients with Fabry disease (PMID: 26252393, 29631605). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Fabry disease in the Spanish population: observational study with detection of 77 patients. | Vieitez I | Orphanet journal of rare diseases | 2018 | PMID: 29631605 |
Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease. | Pan X | PloS one | 2016 | PMID: 27560961 |
Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase. | Warnock DG | PloS one | 2015 | PMID: 26252393 |
Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease. | Auray-Blais C | Molecular genetics and metabolism | 2008 | PMID: 18023222 |
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 |
Text-mined citations for this variant ...
HelpRecord last updated Mar 17, 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.