X-101398501-T-G

Variant names:

• chrX-101398501-T-G
• rs375538532
• NM_000169.3:c.868A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP3 PP5

The NM_000169.3(GLA):​c.868A>C​(p.Met290Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,206,427 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M290I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 8.02
• Publications: 12 publications found

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_000169.3 (GLA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 44 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398499-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222436.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753
• PP5: Variant X-101398501-T-G is Pathogenic according to our data. Variant chrX-101398501-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222434.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.868A>C	p.Met290Leu	missense	Exon 6 of 7	NP_000160.1
	GLA	NM_001406747.1		c.991A>C	p.Met331Leu	missense	Exon 7 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.868A>C	p.Met290Leu	missense	Exon 6 of 6	NP_001393677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.868A>C	p.Met290Leu	missense	Exon 6 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3044T>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.991A>C	p.Met331Leu	missense	Exon 7 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111993 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094434 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359890

African (AFR) AF: 0.00 AC: 0 AN: 26324

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54059

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838684

Other (OTH) AF: 0.00 AC: 0 AN: 45953

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111993 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34141

African (AFR) AF: 0.00 AC: 0 AN: 30791

American (AMR) AF: 0.00 AC: 0 AN: 10539

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53235

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:7

Aug 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.868A>C is a missense variant that changes the amino acid at residue 290 from Methionine to Leucine. This variant has been observed in at least one proband affected with Fabry disease (PMID:3210910;23332617;28069318;21517827). Functional studies have been reported; however, the significance of the findings remain unclear (PMID:21517827;27657681). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify GLA c.868A>C as a likely pathogenic variant.

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Leu). This variant is present in population databases (rs375538532, gnomAD 0.002%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21517827). ClinVar contains an entry for this variant (Variation ID: 222434). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21517827, 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: 23935525, 27773586, 28728877, 29307789). 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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met290Leu variant in GLA has been reported in eight individuals with Fabry disease, has segregated with disease in 7 affected relatives from 2 families (PMID: 23210910, 28069318), and has been identified in 0.0024% (2/81914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375538532). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by Invitae (Variation ID:222434). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21517827). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Met290Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 28302345, 23935525, 22773828, 27560961, 16595074). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS4_supporting, PP1_moderate, PM5_supporting (Richards 2015).

Nov 26, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.868A>C (p.Met290Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183454 control chromosomes (gnomAD). c.868A>C has been reported in the literature in individuals affected with Fabry Disease (e.g. Ferri_2012, Zampetti_2013). These data indicate that the variant is likely to be associated with disease. When expressed in a heterologous HEK293 cell assay, the variant had 11.2% normal activitiy (Ferri_2012). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

not provided Pathogenic:1 Uncertain:2

Jun 26, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: provider interpretation

Seen in 1 patient in our center with dilated cardiomyopathy. Testing was performed at Invitae. Given the weak case data and different phenotype than would be expected for a disease-causing variant in these gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The GLA gene encodes alphagalacotosidase. Mutations in the GLA cause Fabry disease, an X-linked condition characterized by multi-organ dysfunction. Clinical characteristics include left ventricular hypertrophy, kidney failure, peripheral neuropathy, ophthalmologic and sweating abnormalities. The variant has been seen in at least 1 unrelated case of Fabry disease. It has not been reported in any cases of dilated cardiomyopathy. There is weak case data and some functional data. Ferri et al 2011 reported the variant in a patient with clinical findings suggestive of Fabry disease. She was a 34yo, who had "cardiovascular manifestations, psychiatric symptoms, and cardiomyopathy (type not specified). Her alpha-gal A enzyme level was 11nmol/mg/h. The paper noted that the HEK cells harboring the Met290Leu variant had decreased enzyme levels that were recovered with treatment with the pharmacologic chaperone deoxygalactonojirimycin (DGJ). Lukas et al (2013) found that variant resulted in a 18% wild type alpha-gal A level on in vitro assay. The Met at codon 290 is conserved across species. PolyPhen predicts it to be probably damaging. The variant is present in 2 of 89,369 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,00 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 40,064 individuals of European descent (MAF = 0.002%).

Jan 06, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 06, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22004918, 21517827, 25382311, 28069318, 27657681, 23935525, 23210910, 37599028, 37441486, 40276559, 40585426)

Cardiovascular phenotype Pathogenic:1

Jul 14, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M290L variant (also known as c.868A>C), located in coding exon 6 of the GLA gene, results from an A to C substitution at nucleotide position 868. The methionine at codon 290 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in individuals with features consistent with Fabry disease (Ferri L et al. Clin. Genet., 2012 Mar;81:224-33; Zampetti A et al. Clin. Genet., 2013 Sep;84:281-5; Graziani F et al. J Am Soc Echocardiogr, 2017 Mar;30:282-291; Burlina AB et al. Int J Neonatal Screen. 2019 Jun;5(2):24; Gragnaniello V et al. Biomolecules. 2021 Jun;11(7)). In in vitro functional studies, this variant was shown to result in reduced enzyme activity (Ferri L eta l. Clin. Genet. 2012 Mar;81(3):224-33; Lukas J et al. PLoS Genet. 2013 Aug;9(8):e1003632). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the C allele has an overall frequency of 0.0011% (2/183454) total alleles studied, with no hemizygote(s) observed. The highest observed frequency was 0.0024% (2/81914) of European (non-Finnish) alleles. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.63
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.2	L
PhyloP100		8.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.39	N
REVEL	Pathogenic	0.79
Sift	Benign	0.82	T
Sift4G	Benign	0.82	T
Polyphen		0.98	D
Vest4		0.94
MutPred		0.75		Loss of catalytic residue at M290 (P = 0.0189)
MVP		1.0
MPC		1.7
ClinPred		0.49	T
GERP RS		5.9
Varity_R		0.63
gMVP		0.98
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375538532; hg19: chrX-100653489;