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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 23, 2023
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:: RCV001280629.9

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

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

HGVS:

NC_000023.11:g.101398499C>G
NG_007119.1:g.14465G>C
NM_000169.3:c.870G>CMANE SELECT
NM_001199973.2:c.300+3042C>G
NM_001199974.2:c.177+6677C>G
NM_001406747.1:c.993G>C
NM_001406748.1:c.870G>C
NP_000160.1:p.Met290Ile
NP_000160.1:p.Met290Ile
NP_001393676.1:p.Met331Ile
NP_001393677.1:p.Met290Ile
LRG_672t1:c.870G>C
LRG_672:g.14465G>C
LRG_672p1:p.Met290Ile
NC_000023.10:g.100653487C>G
NM_000169.2:c.870G>C
NR_164783.1:n.949G>C
NR_176252.1:n.800G>C
NR_176253.1:n.1007G>C
p.M290I

Protein change:

M290I

Links:

dbSNP: rs869312438

NCBI 1000 Genomes Browser:

rs869312438

Molecular consequence:

NM_001199973.2:c.300+3042C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6677C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.870G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.993G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.870G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.949G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.800G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.1007G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

effect on protein activity [Variation Ontology: 0053]

Condition(s)

Name:: Fabry disease
Synonyms:: ALPHA-GALACTOSIDASE A DEFICIENCY; ANDERSON-FABRY DISEASE; CERAMIDE TRIHEXOSIDASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001467860	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 2, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23935525, 20629180, 32531501, 31449323, 17224688, 22773828, 33527381, 31319156, 33907643 Citation Link,
SCV002054801	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003511409	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 23, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 21517827, 23935525, 22773828, 16595074, 28646478, 31996269, 33527381, 33907643, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001467860

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 2, 2021)

germline

clinical testing

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

Citation Link,

SCV002054801

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 15, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003511409

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 23, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel tools for extraction and validation of disease-related mutations applied to Fabry disease.

Kuipers R, van den Bergh T, Joosten HJ, Lekanne dit Deprez RH, Mannens MM, Schaap PJ.

Hum Mutat. 2010 Sep;31(9):1026-32. doi: 10.1002/humu.21317.

PubMed [citation]

PMID:: 20629180

Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?

Azevedo O, Marques N, Reis L, Cruz I, Craveiro N, Antunes H, Lourenço C, Gomes R, Guerreiro RA, Faria R, Sá F, Lima R, Gaspar P, Faria R, Miltenberger-Miltenyi G, Sousa N, Cunha D; group of investigators.

Am Heart J. 2020 Aug;226:114-126. doi: 10.1016/j.ahj.2020.04.006. Epub 2020 Apr 18.

PubMed [citation]

PMID:: 32531501

See all PubMed Citations (15)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467860.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054801.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003511409.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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