ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.868A>C (p.Met290Leu)
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.
Pathogenic(1); Likely pathogenic(6); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.868A>C (p.Met290Leu)
Variation ID: 222434 Accession: VCV000222434.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101398501 (GRCh38) [ NCBI UCSC ] X: 100653489 (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 26, 2017 May 1, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.868A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Met290Leu missense NM_000169.2(GLA):c.868A>C NM_001199973.2:c.300+3044T>G intron variant NM_001199974.2:c.177+6679T>G intron variant NR_164783.1:n.947A>C non-coding transcript variant NC_000023.11:g.101398501T>G NC_000023.10:g.100653489T>G NG_007119.1:g.14463A>C LRG_672:g.14463A>C LRG_672t1:c.868A>C LRG_672p1:p.Met290Leu - Protein change
- M290L
- Other names
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- Canonical SPDI
- NC_000023.11:101398500:T: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009
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 | 1243 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1274 |
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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jan 9, 2024 | RCV000545099.17 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 8, 2023 | RCV000786316.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2023 | RCV002372207.4 |
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
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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
(Jan 09, 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: SCV000622195.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Leu). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Leu). This variant is present in population databases (rs375538532, gnomAD 0.002%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21517827). ClinVar contains an entry for this variant (Variation ID: 222434). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21517827, 23935525). This variant disrupts the p.Met290 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23935525, 27773586, 28728877, 29307789). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(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: SCV002054802.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Likely pathogenic
(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: SCV001422919.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Met290Leu variant in GLA has been reported in eight individuals with Fabry disease, has segregated with disease in 7 affected relatives from 2 families … (more)
The p.Met290Leu variant in GLA has been reported in eight individuals with Fabry disease, has segregated with disease in 7 affected relatives from 2 families (PMID: 23210910, 28069318), and has been identified in 0.0024% (2/81914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375538532). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by Invitae (Variation ID:222434). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21517827). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Met290Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 28302345, 23935525, 22773828, 27560961, 16595074). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS4_supporting, PP1_moderate, PM5_supporting (Richards 2015). (less)
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Likely pathogenic
(Nov 26, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002765944.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: GLA c.868A>C (p.Met290Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.868A>C (p.Met290Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183454 control chromosomes (gnomAD). c.868A>C has been reported in the literature in individuals affected with Fabry Disease (e.g. Ferri_2012, Zampetti_2013). These data indicate that the variant is likely to be associated with disease. When expressed in a heterologous HEK293 cell assay, the variant had 11.2% normal activitiy (Ferri_2012). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jun 08, 2023)
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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: SCV001873919.2
First in ClinVar: Sep 19, 2021 Last updated: Jun 17, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22004918, 21517827, 23935525, 25382311, 28069318, 23210910, 27657681) (less)
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Uncertain significance
(Jan 06, 2020)
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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: SCV003816855.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Aug 03, 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: SCV001347096.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004825232.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 09, 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: SCV002684480.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.M290L variant (also known as c.868A>C), located in coding exon 6 of the GLA gene, results from an A to C substitution at nucleotide … (more)
The p.M290L variant (also known as c.868A>C), located in coding exon 6 of the GLA gene, results from an A to C substitution at nucleotide position 868. The methionine at codon 290 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have Fabry disease (FD) or features consistent with FD, demonstrating reduced alpha-galactosidase enzyme activity (Ferri L et al. Clin. Genet., 2012 Mar;81:224-33; Zampetti A et al. Clin. Genet., 2013 Sep;84:281-5; Graziani F et al. J Am Soc Echocardiogr, 2017 Mar;30:282-291; Burlina AB et al. Int J Neonatal Screen. 2019 Jun;5(2):24; Gragnaniello V et al. Biomolecules. 2021 Jun;11(7)). In in vitro functional studies, this variant was shown to result in reduced enzyme activity (Ferri L eta l. Clin. Genet. 2012 Mar;81(3):224-33; Lukas J et al. PLoS Genet. 2013 Aug;9(8):e1003632). Another alteration affecting the same amino acid (p.M290I) has also been reported in association with Fabry disease (Colon C et al. Eur. J. Pediatr., 2017 Aug;176:1075-1081; Navarrete-Martínez JI et al. Mol. Genet. Metab., 2017 May;121:16-21). This amino acid position is highly 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)
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Uncertain significance
(Jun 26, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925089.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
Seen in 1 patient in our center with dilated cardiomyopathy. Testing was performed at Invitae. Given the weak case data and different phenotype than would … (more)
Seen in 1 patient in our center with dilated cardiomyopathy. Testing was performed at Invitae. Given the weak case data and different phenotype than would be expected for a disease-causing variant in these gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The GLA gene encodes alphagalacotosidase. Mutations in the GLA cause Fabry disease, an X-linked condition characterized by multi-organ dysfunction. Clinical characteristics include left ventricular hypertrophy, kidney failure, peripheral neuropathy, ophthalmologic and sweating abnormalities. The variant has been seen in at least 1 unrelated case of Fabry disease. It has not been reported in any cases of dilated cardiomyopathy. There is weak case data and some functional data. Ferri et al 2011 reported the variant in a patient with clinical findings suggestive of Fabry disease. She was a 34yo, who had "cardiovascular manifestations, psychiatric symptoms, and cardiomyopathy (type not specified). Her alpha-gal A enzyme level was 11nmol/mg/h. The paper noted that the HEK cells harboring the Met290Leu variant had decreased enzyme levels that were recovered with treatment with the pharmacologic chaperone deoxygalactonojirimycin (DGJ). Lukas et al (2013) found that variant resulted in a 18% wild type alpha-gal A level on in vitro assay. The Met at codon 290 is conserved across species. PolyPhen predicts it to be probably damaging. The variant is present in 2 of 89,369 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,00 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 40,064 individuals of European descent (MAF = 0.002%). (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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Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance. | Viall S | American journal of medical genetics. Part C, Seminars in medical genetics | 2022 | PMID: 36156392 |
Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience. | Gragnaniello V | Biomolecules | 2021 | PMID: 34199132 |
Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS). | Lenders M | Clinical pharmacology and therapeutics | 2020 | PMID: 32198894 |
Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy. | Burlina AB | International journal of neonatal screening | 2019 | PMID: 33072983 |
Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? | Duro G | International journal of molecular sciences | 2018 | PMID: 30477121 |
Inner ear involvement in Fabry disease: Clinical and audiometric evaluation of a large cohort of patients followed in a reference centre. | Rodrigues J | European journal of medical genetics | 2018 | PMID: 29307789 |
Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. | Nowak A | Molecular genetics and metabolism | 2018 | PMID: 28728877 |
Newborn screening for Fabry disease in the north-west of Spain. | Colon C | European journal of pediatrics | 2017 | PMID: 28646478 |
Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system. | Navarrete-Martínez JI | Molecular genetics and metabolism | 2017 | PMID: 28302345 |
Right Ventricular Hypertrophy, Systolic Function, and Disease Severity in Anderson-Fabry Disease: An Echocardiographic Study. | Graziani F | Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography | 2017 | PMID: 28069318 |
Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. | Nowak A | Molecular genetics and metabolism | 2017 | PMID: 27773586 |
Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease. | Pan X | PloS one | 2016 | PMID: 27560961 |
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 |
Vascular endothelial growth factor (VEGF-a) in Fabry disease: association with cutaneous and systemic manifestations with vascular involvement. | Zampetti A | Cytokine | 2013 | PMID: 23332617 |
Mutation identification of Fabry disease in families with other lysosomal storage disorders. | Zampetti A | Clinical genetics | 2013 | PMID: 23210910 |
α-Galactosidase aggregation is a determinant of pharmacological chaperone efficacy on Fabry disease mutants. | Siekierska A | The Journal of biological chemistry | 2012 | PMID: 22773828 |
Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. | Ferri L | Clinical genetics | 2012 | PMID: 21517827 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fe347b47-9c78-4876-8e24-213504db5d99 | - | - | - | - |
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Text-mined citations for rs375538532 ...
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.