NM_000169.3(GLA):c.870G>A (p.Met290Ile) AND Fabry disease

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jan 13, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001205029.12

Allele description [Variation Report for NM_000169.3(GLA):c.870G>A (p.Met290Ile)]

NM_000169.3(GLA):c.870G>A (p.Met290Ile)

Genes:
RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq22.1
Genomic location:
Preferred name:
NM_000169.3(GLA):c.870G>A (p.Met290Ile)
HGVS:
  • NC_000023.11:g.101398499C>T
  • NG_007119.1:g.14465G>A
  • NM_000169.3:c.870G>AMANE SELECT
  • NM_001199973.2:c.300+3042C>T
  • NM_001199974.2:c.177+6677C>T
  • NM_001406747.1:c.993G>A
  • NM_001406748.1:c.870G>A
  • NP_000160.1:p.Met290Ile
  • NP_000160.1:p.Met290Ile
  • NP_001393676.1:p.Met331Ile
  • NP_001393677.1:p.Met290Ile
  • LRG_672t1:c.870G>A
  • LRG_672:g.14465G>A
  • LRG_672p1:p.Met290Ile
  • NC_000023.10:g.100653487C>T
  • NM_000169.2:c.870G>A
  • NR_164783.1:n.949G>A
  • NR_176252.1:n.800G>A
  • NR_176253.1:n.1007G>A
  • p.M290I
Protein change:
M290I
Links:
dbSNP: rs869312438
NCBI 1000 Genomes Browser:
rs869312438
Molecular consequence:
  • NM_001199973.2:c.300+3042C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+6677C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.870G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.993G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.870G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.949G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.800G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.1007G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
effect on protein activity [Variation Ontology: 0053]
Observations:
1

Condition(s)

Name:
Fabry disease
Synonyms:
Angiokeratoma, diffuse; Anderson-Fabry disease; Hereditary dystopic lipidosis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001376265Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 13, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002081337Natera, Inc.
no assertion criteria provided
Likely pathogenic
(Jan 6, 2021) 		germlineclinical testing

SCV004839356All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Dec 6, 2023) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes.

Nowak A, Mechtler TP, Desnick RJ, Kasper DC.

Mol Genet Metab. 2017 Jan - Feb;120(1-2):57-61. doi: 10.1016/j.ymgme.2016.10.006. Epub 2016 Oct 19.

PubMed [citation]
PMID:
27773586

Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.

Lukas J, Giese AK, Markoff A, Grittner U, Kolodny E, Mascher H, Lackner KJ, Meyer W, Wree P, Saviouk V, Rolfs A.

PLoS Genet. 2013;9(8):e1003632. doi: 10.1371/journal.pgen.1003632. Epub 2013 Aug 1.

PubMed [citation]
PMID:
23935525
PMCID:
PMC3731228
See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001376265.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 23935525, 27773586, 28728877, 29307789). ClinVar contains an entry for this variant (Variation ID: 222435). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 22773828, 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: 21517827; Invitae). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV002081337.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004839356.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (9)

Description

The c.870G>A (p.Met290Ile) variant in the GLA gene is located in the exon 6 of the GLA gene and is predicted to replace methionine with isoleucine at codon 290 of the GLA protein. This variant has been identified in many individuals with Fabry disease (PMID: 31996269, 33907643, 36745055, 32531501, 36564230, 28728877, 29307789). Experimental studies have shown that this missense change affects GLA function (PMID: 22773828). This variant has not been detected in the general population according to gnomAD. In silico prediction algorithm suggests that this variant may have deleterious impact on protein structure and function (REVEL score 0.884). A different variant affecting the same amino acid residue Met290 (c.870G>C, p.Met290Ile) has been determined to be likely pathogenic in ClinVar according to ACMG guidelines. Therefore, the c.870G>A (p.Met290Ile) variant in the GLA gene has been classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024