ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.3G>A (p.Met1Ile)
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.3G>A (p.Met1Ile)
Variation ID: 1065155 Accession: VCV001065155.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101407901 (GRCh38) [ NCBI UCSC ] X: 100662889 (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 30, 2021 Aug 11, 2024 May 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Met1Ile missense initiator codon variant NM_001199973.2:c.301-4035C>T intron variant NM_001199974.2:c.178-4035C>T intron variant NM_001406747.1:c.3G>A NP_001393676.1:p.Met1Ile missense initiator codon variant NM_001406748.1:c.3G>A NP_001393677.1:p.Met1Ile missense initiator codon variant NM_001406749.1:c.3G>A NP_001393678.1:p.Met1Ile missense initiator codon variant NR_164783.1:n.25G>A non-coding transcript variant NR_176252.1:n.25G>A non-coding transcript variant NR_176253.1:n.25G>A non-coding transcript variant NC_000023.11:g.101407901C>T NC_000023.10:g.100662889C>T NG_007119.1:g.5063G>A NG_016327.1:g.4699C>T LRG_672:g.5063G>A LRG_672t1:c.3G>A LRG_672p1:p.Met1Ile - Protein change
- M1I
- Other names
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- Canonical SPDI
- NC_000023.11:101407900:C:T
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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
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. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7 | 1257 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1295 |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2022 | RCV001375575.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 21, 2024 | RCV004629626.1 |
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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Likely pathogenic
(Apr 08, 2021)
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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: SCV001572466.2
First in ClinVar: Apr 30, 2021 Last updated: Sep 03, 2023 |
Comment:
Variant summary: GLA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: GLA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183327 control chromosomes. c.3G>A has been reported in the literature in at-least two male individuals affected with Fabry Disease (example, Blanch_1996, Kobayashi_2014). The variant was reported as a de-novo occurrence in one of these affected males (Kobayashi_2014). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in carrier females (Hossain_2019). The most pronounced variant effect results in 22-45% of normal activity in carrier females. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Dec 01, 2022)
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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: SCV003445179.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1065155). Disruption of the initiator codon … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1065155). Disruption of the initiator codon has been observed in individual(s) with Fabry disease (PMID: 8807334, 12175777, 27896102, 28275245, 31372342). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GLA mRNA. The next in-frame methionine is located at codon 42. (less)
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Pathogenic
(May 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV005123517.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the GLA gene and results from a G to A … (more)
The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the GLA gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in individuals with Fabry disease, including a de novo occurrence in one individual (Blanch LC. Hum Mutat. 1996;8(1):38-43; Kobayashi M. Mol Genet Metab Rep. 2014 Aug 2;1:283-287). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (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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Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene. | Hossain MA | Molecular genetics and metabolism reports | 2019 | PMID: 31372342 |
Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients. | Nagamatsu K | Journal of human genetics | 2017 | PMID: 28275245 |
Frequency of de novo mutations in Japanese patients with Fabry disease. | Kobayashi M | Molecular genetics and metabolism reports | 2014 | PMID: 27896102 |
Structural basis of Fabry disease. | Garman SC | Molecular genetics and metabolism | 2002 | PMID: 12359124 |
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. | Shabbeer J | Molecular genetics and metabolism | 2002 | PMID: 12175777 |
A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. | Blanch LC | Human mutation | 1996 | PMID: 8807334 |
Text-mined citations for rs2147487910 ...
HelpRecord last updated Nov 03, 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.