This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Fabry disease or hypertrophic cardiomyopathy (PMID: 23935525, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 835100). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.525C>A (p.Asp175Glu)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000169.3(GLA):c.525C>A (p.Asp175Glu)
Variation ID: 835100 Accession: VCV000835100.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq22.1 X: 101401654 (GRCh38) [ NCBI UCSC ] X: 100656642 (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 Apr 15, 2020 Oct 20, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.525C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Asp175Glu missense NM_001199973.2:c.300+6197G>T intron variant NM_001199974.2:c.177+9832G>T intron variant NM_001406747.1:c.648C>A NP_001393676.1:p.Asp216Glu missense NM_001406748.1:c.525C>A NP_001393677.1:p.Asp175Glu missense NM_001406749.1:c.648C>A NP_001393678.1:p.Asp216Glu missense NR_164783.1:n.547C>A non-coding transcript variant NR_176252.1:n.547C>A non-coding transcript variant NR_176253.1:n.547C>A non-coding transcript variant NC_000023.11:g.101401654G>T NC_000023.10:g.100656642G>T NG_007119.1:g.11310C>A LRG_672:g.11310C>A LRG_672t1:c.525C>A LRG_672p1:p.Asp175Glu - Protein change
- D175E, D216E
- Other names
- -
- Canonical SPDI
- NC_000023.11:101401653:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 |
7 | 1257 | |
| RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1295 |
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. |
|---|---|---|---|---|
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 31, 2023 | RCV001035911.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 5, 2023 | RCV003372939.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 1, 2024 | RCV004597948.3 |
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
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054353.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Uncertain significance
(Dec 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002815886.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Dec 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001199251.3
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Fabry disease or hypertrophic cardiomyopathy (PMID: 23935525, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 835100). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(May 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001358881.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 175 of the GLA protein. Computational prediction suggests that this variant may not impact … (more)
This missense variant replaces aspartic acid with glutamic acid at codon 175 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). Functional studies have shown that this variant results in a partially reduced enzyme activity (PMID: 31036492, 31367522, 32023956, 32531501). This variant has been reported in an individual affected with Fabry disease (PMID: 23935525) and in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has been identified in 1/183473 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Sep 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004098463.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.D175E variant (also known as c.525C>A), located in coding exon 3 of the GLA gene, results from a C to A substitution at nucleotide … (more)
The p.D175E variant (also known as c.525C>A), located in coding exon 3 of the GLA gene, results from a C to A substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Patel V et al. Heart, 2015 Jun;101:961-6; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Azevedo O et al. Am Heart J, 2020 Aug;226:114-126). In vitro assays showed this alteration has >50% enzyme activity compared to wild-type (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183473) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0036% (1/27429) of Latino alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005093253.3
First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024 |
Comment:
GLA: PM2, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Sep 17, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081347.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 175 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). Functional studies have shown that this variant results in a partially reduced enzyme activity (PMID: 31036492, 31367522, 32023956, 32531501). This variant has been reported in an individual affected with Fabry disease (PMID: 23935525) and in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has been identified in 1/183473 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.D175E variant (also known as c.525C>A), located in coding exon 3 of the GLA gene, results from a C to A substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Patel V et al. Heart, 2015 Jun;101:961-6; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Azevedo O et al. Am Heart J, 2020 Aug;226:114-126). In vitro assays showed this alteration has >50% enzyme activity compared to wild-type (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183473) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0036% (1/27429) of Latino alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
GLA: PM2, PS3:Supporting
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. |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Fabry disease or hypertrophic cardiomyopathy (PMID: 23935525, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 835100). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 175 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). Functional studies have shown that this variant results in a partially reduced enzyme activity (PMID: 31036492, 31367522, 32023956, 32531501). This variant has been reported in an individual affected with Fabry disease (PMID: 23935525) and in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has been identified in 1/183473 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.D175E variant (also known as c.525C>A), located in coding exon 3 of the GLA gene, results from a C to A substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Patel V et al. Heart, 2015 Jun;101:961-6; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Azevedo O et al. Am Heart J, 2020 Aug;226:114-126). In vitro assays showed this alteration has >50% enzyme activity compared to wild-type (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183473) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0036% (1/27429) of Latino alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
GLA: PM2, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy? | Azevedo O | American heart journal | 2020 | PMID: 32531501 |
| 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 |
| The migalastat GLP-HEK assay is the gold standard for determining amenability in patients with Fabry disease. | Schiffmann R | Molecular genetics and metabolism reports | 2019 | PMID: 31367522 |
| Inter-assay variability influences migalastat amenability assessments among Fabry disease variants. | Oommen S | Molecular genetics and metabolism | 2019 | PMID: 31036492 |
| Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
| Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry Disease. | Patel V | Heart (British Cardiac Society) | 2015 | PMID: 25655062 |
| 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 |
Text-mined citations for rs782722844 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.