ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.47T>C (p.Leu16Pro)
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.47T>C (p.Leu16Pro)
Variation ID: 1743191 Accession: VCV001743191.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101407857 (GRCh38) [ NCBI UCSC ] X: 100662845 (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 Nov 29, 2022 Feb 14, 2024 Mar 11, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.47T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Leu16Pro missense NM_001199973.2:c.301-4079A>G intron variant NM_001199974.2:c.178-4079A>G intron variant NM_001406747.1:c.47T>C NP_001393676.1:p.Leu16Pro missense NM_001406748.1:c.47T>C NP_001393677.1:p.Leu16Pro missense NM_001406749.1:c.47T>C NP_001393678.1:p.Leu16Pro missense NR_164783.1:n.69T>C non-coding transcript variant NR_176252.1:n.69T>C NR_176253.1:n.69T>C NC_000023.11:g.101407857A>G NC_000023.10:g.100662845A>G NG_007119.1:g.5107T>C NG_016327.1:g.4655A>G LRG_672:g.5107T>C LRG_672t1:c.47T>C LRG_672p1:p.Leu16Pro - Protein change
- L16P
- Other names
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- Canonical SPDI
- NC_000023.11:101407856:A:G
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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
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. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1235 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1263 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2018 | RCV002337874.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV003096472.3 |
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
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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
(Sep 12, 2018)
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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: SCV002638391.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.L16P variant (also known as c.47T>C), located in coding exon 1 of the GLA gene, results from a T to C substitution at nucleotide … (more)
The p.L16P variant (also known as c.47T>C), located in coding exon 1 of the GLA gene, results from a T to C substitution at nucleotide position 47. The leucine at codon 16 is replaced by proline, an amino acid with similar properties. This variant segregated with disease in tested individuals in a family reported to have Fabry disease, with features including cerebrovascular findings, unspecified renal and cardiac involvement, and reduced alpha-galactosidase A activity in males with this variant (Garzuly F et al. Brain, 2005 Sep;128:2078-83). In another study, this variant was reported to result in undetectable alpha-galactosidase A in HEK-293 cell lysates (Benjamin ER et al. Genet. Med., 2017 04;19:430-438). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 11, 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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Invitae
Accession: SCV003445176.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu16 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 30386727, 30988410), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Fabry disease (PMID: 15947062). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 16 of the GLA protein (p.Leu16Pro). (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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Mutation spectrum of α-Galactosidase gene in Japanese patients with Fabry disease. | Kobayashi M | Journal of human genetics | 2019 | PMID: 30988410 |
Fabry disease in a Japanese population-molecular and biochemical characteristics. | Sakuraba H | Molecular genetics and metabolism reports | 2018 | PMID: 30386727 |
The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. | Benjamin ER | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27657681 |
Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations. | Riera C | Proteins | 2015 | PMID: 25382311 |
Megadolichobasilar anomaly with thrombosis in a family with Fabry's disease and a novel mutation in the alpha-galactosidase A gene. | Garzuly F | Brain : a journal of neurology | 2005 | PMID: 15947062 |
Text-mined citations for this variant ...
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.