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NM_000169.2(GLA):c.593T>C (p.Ile198Thr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Sep 2, 2021)
Last evaluated:
Aug 7, 2020
Accession:
VCV000167142.5
Variation ID:
167142
Description:
single nucleotide variant
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NM_000169.2(GLA):c.593T>C (p.Ile198Thr)

Allele ID
177172
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
Xq22.1
Genomic location
X: 101400712 (GRCh38) GRCh38 UCSC
X: 100655700 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P06280:p.Ile198Thr
NC_000023.11:g.101400712A>G
NG_007119.1:g.12252T>C
... more HGVS
Protein change
-
Other names
-
Canonical SPDI
NC_000023.11:101400711:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Links
ClinGen: CA021809
UniProtKB: P06280#VAR_077390
dbSNP: rs727503950
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 criteria provided, single submitter Oct 24, 2017 RCV000723576.2
Conflicting interpretations of pathogenicity 5 criteria provided, conflicting interpretations Aug 7, 2020 RCV000153323.12
drug response 1 no assertion criteria provided Jan 1, 2014 RCV000209729.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
GLA Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
11 860
RPL36A-HNRNPH2 - - - GRCh38
GRCh37
- 865

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Apr 27, 2018)
criteria provided, single submitter
Method: clinical testing
Fabry disease
Allele origin: germline
Invitae
Accession: SCV000819448.1
Submitted: (Aug 29, 2018)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces isoleucine with threonine at codon 198 of the GLA protein (p.Ile198Thr). The isoleucine residue is highly conserved and there is a … (more)
Likely pathogenic
(Oct 24, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000202803.7
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (3)
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(Dec 31, 2019)
criteria provided, single submitter
Method: clinical testing
Fabry disease
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362671.1
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (8)
Comment:
Variant summary: GLA c.593T>C (p.Ile198Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Uncertain significance
(Aug 07, 2020)
criteria provided, single submitter
Method: clinical testing
Fabry disease
Allele origin: germline
Color Health, Inc
Accession: SCV001735629.1
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant replaces isoleucine with threonine at codon 198 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
Likely pathogenic
(Jan 01, 2014)
no assertion criteria provided
Method: research
Fabry's disease
Allele origin: inherited
Albrecht-Kossel-Institute,Medical University Rostock
Accession: SCV000246053.1
Submitted: (Sep 23, 2015)
Evidence details
Publications
PubMed (1)
drug response
Pharmacological Chaperone response: yes
(Jan 01, 2014)
no assertion criteria provided
Method: research
deoxygalactonojirimycin response
Drug used for Fabry disease
Allele origin: inherited
Albrecht-Kossel-Institute,Medical University Rostock
Accession: SCV000246054.1
Submitted: (Sep 23, 2015)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Jan 22, 2020)
no assertion criteria provided
Method: curation
Fabry disease
(X-linked inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422641.1
Submitted: (Mar 09, 2020)
Comment:
X-linked inheritance (primarily recessive with milder female expression)
Evidence details
Publications
PubMed (4)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Ile198Thr variant in GLA has been reported in 2 males and 2 females with Fabry disease (PMID: 26415523, 25974833, 21587323), and has been identified … (more)
Pathogenic
(Nov 11, 2019)
no assertion criteria provided
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001822500.1
Submitted: (Sep 02, 2021)
Evidence details
Comment:
Expression studies found this variant is associated with 38.7% residual enzyme activity (Lukas et al., 2016); Not observed at a significant frequency in large population … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Inter-assay variability influences migalastat amenability assessments among Fabry disease variants. Oommen S Molecular genetics and metabolism 2019 PMID: 31036492
Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ. Ferri L Clinica chimica acta; international journal of clinical chemistry 2018 PMID: 29476735
LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. Pettazzoni M PloS one 2017 PMID: 28749998
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. Lukas J Human mutation 2016 PMID: 26415523
X-chromosome inactivation in female patients with Fabry disease. Echevarria L Clinical genetics 2016 PMID: 25974833
Raynaud's phenomenon associated with Fabry disease. Germain DP Journal of inherited metabolic disease 2015 PMID: 25511234
Urinary biomarker investigation in children with Fabry disease using tandem mass spectrometry. Auray-Blais C Clinica chimica acta; international journal of clinical chemistry 2015 PMID: 25149322
Fabry or not Fabry--a question of ascertainment. Houge G European journal of human genetics : EJHG 2011 PMID: 21587323
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9dbd7f04-6261-4c3e-8e0a-6641530463e9 - - - -

Text-mined citations for rs727503950...

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These 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 Sep 18, 2021