ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.1033_1034del (p.Ser345fs)
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.1033_1034del (p.Ser345fs)
Variation ID: 92538 Accession: VCV000092538.18
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: Xq22.1 X: 101398065-101398066 (GRCh38) [ NCBI UCSC ] X: 100653053-100653054 (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 Jul 24, 2016 Feb 14, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.1033_1034del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Ser345fs frameshift NM_000169.2:c.1033_1034delTC NM_001199973.2:c.300+2608GA[2] intron variant NM_001199974.2:c.177+6243GA[2] intron variant NR_164783.1:n.1108TC[2] non-coding transcript variant NC_000023.11:g.101398066AG[2] NC_000023.10:g.100653054AG[2] NG_007119.1:g.14894TC[2] LRG_672:g.14894TC[2] LRG_672t1:c.1033_1034del - Protein change
- S345fs
- Other names
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- Canonical SPDI
- NC_000023.11:101398064:GAGAGAG:GAGAG
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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 | 1212 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1240 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000078263.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2021 | RCV000236755.10 |
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
(Jun 03, 2016)
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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: SCV000695728.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The GLA c.1033_1034delTC (p.Ser345Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense … (more)
Variant summary: The GLA c.1033_1034delTC (p.Ser345Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87610 control chromosomes while it was reported in several Fabry patients indicating pathogenicity. GLA activity, GLA protein levels were severely decreased in affected carriers with Lyso-Gb3 being elevated further supporting pathogenicity. Additionally, a clinical diagnostic laboratory classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 20, 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: SCV000110103.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Sep 21, 2015)
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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: SCV000292562.10
First in ClinVar: Jul 24, 2016 Last updated: Dec 15, 2018 |
Comment:
The c.1033_1034delTC mutation in the GLA gene has been reported previously in several unrelated males with Fabry disease and significantly reduced a-galactosidase activity (Germain et … (more)
The c.1033_1034delTC mutation in the GLA gene has been reported previously in several unrelated males with Fabry disease and significantly reduced a-galactosidase activity (Germain et al., 1996; Pereira et al., 2007; Tsukimura et al., 2014). The deletion causes a frameshift starting with codon Serine 345, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Ser345ArgfsX29. This mutation is predicted to cause loss of normal protein function through protein truncation. This result is expected to be consistent with a diagnosis of Fabry disease (less)
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Pathogenic
(Jan 19, 2021)
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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: SCV002024319.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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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: SCV002054380.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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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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Invitae
Accession: SCV001232317.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser345Argfs*29) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ser345Argfs*29) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the GLA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Fabry disease (PMID: 8931708, 23935525). This variant is also known as L344-X28-Stop and c.1029-1030delTC. ClinVar contains an entry for this variant (Variation ID: 92538). This variant disrupts a region of the GLA protein in which other variant(s) (p.Val376Profs*10) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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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Development of a highly sensitive immuno-PCR assay for the measurement of α-galactosidase A protein levels in serum and plasma. | Nakano S | PloS one | 2013 | PMID: 24236025 |
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 |
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 |
Molecular analysis in Fabry disease in Spain: fifteen novel GLA mutations and identification of a homozygous female. | Rodríguez-Marí A | Human mutation | 2003 | PMID: 12938095 |
Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype. | Ashley GA | Journal of human genetics | 2001 | PMID: 11322659 |
Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. | Germain D | Human genetics | 1996 | PMID: 8931708 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs398123198 ...
HelpRecord last updated Apr 15, 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.