ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.870G>C (p.Met290Ile)
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(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000169.3(GLA):c.870G>C (p.Met290Ile)
Variation ID: 222436 Accession: VCV000222436.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq22.1 X: 101398499 (GRCh38) [ NCBI UCSC ] X: 100653487 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 16, 2018 Feb 20, 2024 Apr 23, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000169.3:c.870G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Met290Ile missense NM_001199973.2:c.300+3042C>G intron variant NM_001199974.2:c.177+6677C>G intron variant NR_164783.1:n.949G>C non-coding transcript variant NC_000023.11:g.101398499C>G NC_000023.10:g.100653487C>G NG_007119.1:g.14465G>C LRG_672:g.14465G>C LRG_672t1:c.870G>C LRG_672p1:p.Met290Ile - Protein change
- M290I
- Other names
- -
- Canonical SPDI
- NC_000023.11:101398498:C:G
-
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]
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1217 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1245 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 21, 2021 | RCV000733247.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 23, 2023 | RCV001280629.7 |
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861291.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 5
Sex: mixed
|
|
Likely pathogenic
(Jul 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001467860.2
First in ClinVar: Jan 07, 2021 Last updated: Jul 10, 2021 |
Comment:
Variant summary: GLA c.870G>C (p.Met290Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.870G>C (p.Met290Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183451 control chromosomes (gnomAD). c.870G>C has been reported in the literature in a female patient with hypertrophic cardiomyopathy in whom lysomal inclusions were reportedly demonstrated in the myocardium (Azevedo_2020), two female patients with late onset Fabry phenotype (Nowak_2019), two female heterozygotes with significant symptoms of Fabry disease and one of whom was diagnosed with the Classic form the disease (Wang_2007, Delarosa-Rodriguez_2021) and also in a female heterozygote without any classic Fabry disease symptoms (Silva_2021). However, none of these studies report X-inactivation studies performed on female patients. Several publications report conflicting experimental evidence evaluating an impact on protein function. Enzymatic activity of Alpha Galactosidase A was found to be reduced at between 10-30% of normal activity in patient derived leukocytes while the activity levels in patient derived plasma were within the reportable normal range (Azevedo_2020). In addition, in an in vitro functional assay another nucleotide change (c.870G>A) with the same codon and amino acid effect (p.Met290Ile) was found to have approximately 40% of enzymatic activity compared to wild-type (Lukas_2013) while another assay expressing the variant in HEK-cells reported activity levels at 68% of normal (Nowak_2019). One of these studies reports the minimal alpha-Gal activity required to avoid Fabry disease as being between 30-35% of the mean control (Nowak_2019), although they express ambiguity on the extent the alpha-Gal activity in HEK 293 cells correlates with in-vivo activities in affected males with Fabry disease. A different nucleotide change resulting in the same protein effect, namely, GLA c.870G>A (p.M290I) has been reported as likely pathogenic in ClinVar and also seen in patients with Fabry Disease in the HGMD database. In addition, several other variants affecting the same codon and nearby codons (example: p.M290L, p.M290V, p.I289V, p.A291T) have been reported in HGMD and ClinVar suggesting this domain might be clinically significant. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, due to a paucity of evidence supporting a penetrant pathogenic outcome in affected males, and conflicting functional evidence, the variant was classified as likely pathogenic. (less)
|
|
Uncertain significance
(Oct 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001803521.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Reported as heterozygous in an individual with late-onset Fabry disease with normal alpha galactosidase A activity and normal LysoGb2 levels (Nowak et al., 2017); Reported … (more)
Reported as heterozygous in an individual with late-onset Fabry disease with normal alpha galactosidase A activity and normal LysoGb2 levels (Nowak et al., 2017); Reported as heterozygous in an individual with late-onset Fabry disease and also present in the asymptomatic sisters (Azevedo et al., 2020); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27773586, 32531501, 28728877, 31519519) (less)
|
|
Likely pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054801.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
Likely pathogenic
(Dec 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003834640.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Apr 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003511409.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met290 amino acid residue in GLA. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. 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: 21517827, 23935525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GLA function (PMID: 22773828). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. ClinVar contains an entry for this variant (Variation ID: 222436). This missense change has been observed in individual(s) with Fabry disease (PMID: 16595074, 28646478, 31996269, 33527381, 33907643). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Ile). (less)
|
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 |
---|---|---|---|---|
Fabry Disease p.M290I Mutation is Related to Organ Involvement: A Case Report. | Silva F | Cureus | 2021 | PMID: 33907643 |
Accuracy diagnosis improvement of Fabry disease from dried blood spots: Enzyme activity, lyso-Gb3 accumulation and GLA gene sequencing. | Delarosa-Rodríguez R | Clinical genetics | 2021 | PMID: 33527381 |
Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy? | Azevedo O | American heart journal | 2020 | PMID: 32531501 |
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 |
Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort. | Nowak A | Journal of inherited metabolic disease | 2020 | PMID: 31449323 |
Global glycosphingolipid analysis in urine and plasma of female Fabry disease patients. | Heywood WE | Biochimica et biophysica acta. Molecular basis of disease | 2019 | PMID: 31319156 |
Newborn screening for Fabry disease in the north-west of Spain. | Colon C | European journal of pediatrics | 2017 | PMID: 28646478 |
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 |
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 |
Novel tools for extraction and validation of disease-related mutations applied to Fabry disease. | Kuipers R | Human mutation | 2010 | PMID: 20629180 |
Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. | Wang RY | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17224688 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs869312438 ...
HelpRecord last updated Mar 17, 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.