ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.1102G>A (p.Ala368Thr)
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.
Uncertain significance(4); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.1102G>A (p.Ala368Thr)
Variation ID: 42451 Accession: VCV000042451.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101397997 (GRCh38) [ NCBI UCSC ] X: 100652985 (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 Mar 8, 2017 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.1102G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Ala368Thr missense NM_001199973.2:c.300+2540C>T intron variant NM_001199974.2:c.177+6175C>T intron variant NR_164783.1:n.1181G>A non-coding transcript variant NC_000023.11:g.101397997C>T NC_000023.10:g.100652985C>T NG_007119.1:g.14967G>A LRG_672:g.14967G>A LRG_672t1:c.1102G>A - Protein change
- A368T
- Other names
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- Canonical SPDI
- NC_000023.11:101397996:C: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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0.00053 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00041
1000 Genomes Project 0.00053
1000 Genomes Project 30x 0.00083
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 |
6 | 1239 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1270 |
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
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000035300.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 25, 2024 | RCV000463728.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 8, 2019 | RCV001507537.6 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 16, 2023 | RCV002426548.4 |
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 benign
(Apr 08, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000513155.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500542.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 30, 2024 |
Comment:
Variant summary: GLA c.1102G>A (p.Ala368Thr) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded … (more)
Variant summary: GLA c.1102G>A (p.Ala368Thr) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 1208524 control chromosomes, including 15 hemizygotes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLA causing Fabry Disease (4.9e-05 vs 0.005), allowing no conclusion about variant significance. c.1102G>A has been reported in the literature in male and female individuals suspected or affected with Fabry Disease (e.g. Turaca_2012, Lukas_2013, Pereira_2014, Silva_2016, Stiles_2020, Varela_2020) and an individual affected with dilated cardiomyopathy (Pugh_2014). One of the reported male patients was a 73-year-old undergoing hemodialysis for approximately 5 years who denied experiencing classical FD symptoms; clinical manifestations of the patient included: Cornea verticillata, Fabry nephropathy and Left ventricular hypertrophy (Silva_2016). These reports do not provide unequivocal conclusions about association of the variant with Fabry Disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal enzyme activity (e.g. Lukas_2013, Benjamin_2017, Oommen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27657681, 29330335, 37441486, 23935525, 30985853, 31036492, 24334114, 24503780, 27576502, 32418857, 22551898, 31996269). ClinVar contains an entry for this variant (Variation ID: 42451). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Nov 16, 2023)
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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: SCV002740601.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jul 06, 2012)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058948.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2017 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The Ala368Thr varia nt in GLA has been identified in 2/3835 African American chromosomes from a broa … (more)
Variant classified as Uncertain Significance - Favor Benign. The Ala368Thr varia nt in GLA has been identified in 2/3835 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS). Alanine (Ala) at position 368 is not conserved in mammals with other spec ies carrying various other amino acid residues and 1 species (atlantic salmon) c arries a threonine (Thr; this variant), suggesting that this change may be toler ated. In addition, computational analyses (biochemical amino acid properties, Al ignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the frequency of this variant and lack of amino acid conservation su ggests that it may be more likely benign, but additional information is needed t o fully assess its clinical significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 08, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713142.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Likely benign
(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: SCV002054471.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Likely benign
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422795.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Ala368Thr variant in GLA has been reported in 1 African American female with Fabry Disease (PMID: 24503780), and has been identified in 0.1% (19/18974) … (more)
The p.Ala368Thr variant in GLA has been reported in 1 African American female with Fabry Disease (PMID: 24503780), and has been identified in 0.1% (19/18974) of African chromosomes, including 8 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144994244). This variant has also been reported in ClinVar as a VUS by Invitae and the Laboratory for Molecular Medicine (Partners Healthcare) and likely benign by GeneDx (Variation ID:42451). In vitro functional studies provide some evidence that the p.Ala368Thr variant may not impact protein function (PMID: 23935525, 24334114, 27576502). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individual with this variant has an alternative molecular basis for Fabry disease, suggesting this variant may not cause the disease (PMID: 24503780). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BS3_supporting, BP5 (Richards 2015). (less)
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Uncertain significance
(May 10, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001360072.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 368 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with threonine at codon 368 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in-vitro functional assay using transfected HEK-293 cells has shown that this variant causes a small decrease in alpha-galactosidase activity (PMID: 31996269). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780), in a female suspected to be affected with Fabry disease (PMID: 23935525), in a male undergoing hemodialysis (PMID: 27576502), and in an unaffected female (PMID: 32418857). This variant has been identified in 19/205199 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jan 25, 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: SCV000543777.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
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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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Population Frequency of Undiagnosed Fabry Disease in the General Population. | Kermond-Marino A | Kidney international reports | 2023 | PMID: 37441486 |
In Vitro and In Vivo Amenability to Migalastat in Fabry Disease. | Lenders M | Molecular therapy. Methods & clinical development | 2020 | PMID: 32995357 |
A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. | Stiles AR | Molecular genetics and metabolism | 2020 | PMID: 32418857 |
Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease. | Lukas J | International journal of molecular sciences | 2020 | PMID: 32023956 |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients. | Varela P | Orphanet journal of rare diseases | 2020 | PMID: 31996269 |
Inter-assay variability influences migalastat amenability assessments among Fabry disease variants. | Oommen S | Molecular genetics and metabolism | 2019 | PMID: 31036492 |
Sensitivity, advantages, limitations, and clinical utility of targeted next-generation sequencing panels for the diagnosis of selected lysosomal storage disorders. | Málaga DR | Genetics and molecular biology | 2019 | PMID: 30985853 |
Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017. | Doheny D | Journal of medical genetics | 2018 | PMID: 29330335 |
Simple and efficient screening of patients with Fabry disease with high resolution melting. | Pasqualim G | Clinical biochemistry | 2018 | PMID: 29305833 |
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 |
Targeted Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening. | Silva CA | Nephron | 2016 | PMID: 27576502 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Lysosome-associated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease. | Pereira EM | Gene | 2014 | PMID: 24334114 |
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 |
New mutations in the GLA gene in Brazilian families with Fabry disease. | Turaça LT | Journal of human genetics | 2012 | PMID: 22551898 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/48697a7a-16bd-4245-afe6-f3350a8bf880 | - | - | - | - |
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Text-mined citations for rs144994244 ...
HelpRecord last updated May 12, 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.