chrX-101403941-C-T

Variant names:

• chrX-101403941-C-T
• rs781838005
• NM_000169.3:c.239G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000169.3(GLA):​c.239G>A​(p.Gly80Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,032 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G80A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:11 O:1
• Conservation: PhyloP100: 7.90
• Publications: 5 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.982

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.239G>A	p.Gly80Asp	missense	Exon 2 of 7	NP_000160.1
	GLA	NM_001406747.1		c.362G>A	p.Gly121Asp	missense	Exon 3 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.239G>A	p.Gly80Asp	missense	Exon 2 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.239G>A	p.Gly80Asp	missense	Exon 2 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-7995C>T		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.362G>A	p.Gly121Asp	missense	Exon 3 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112527 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096452 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361818

African (AFR) AF: 0.00 AC: 0 AN: 26359

American (AMR) AF: 0.0000568 AC: 2 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840533

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112580 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34760

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31065

American (AMR) AF: 0.0000941 AC: 1 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53295

Other (OTH) AF: 0.00 AC: 0 AN: 1533

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:3 Uncertain:6

Jan 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that this variant leads to 29.3% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported an individual affected with late-onset Fabry disease with renal symptoms (PMID: 33527381). It has also been reported in three individuals referred for Fabry disease genetic testing (PMID: 26415523), one individual affected with sudden unexplained death (PMID: 29247119), eight unrelated newborns without a family history of Fabry disease (PMID: 30093709), and in one individual undergoing dialysis but not diagnosed with Fabry disease (PMID: 31392112). Most of these carriers were males who usually showed high residual GLA enzyme activity and slightly elevated globotriaosylsphingosine (lyso-Gb3) levels (PMID: 26415523, 30093709, 31392112, 33527381). This variant has not been identified 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.

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 80 of the GLA protein (p.Gly80Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with predominantly late onset Fabry disease and/or low alpha-galactosidase activity (PMID: 26415523, 33527381; internal data). ClinVar contains an entry for this variant (Variation ID: 217380). 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) has been performed 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: 26415523). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 25, 2025

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.239G>A (p.Gly80Asp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 183388 control chromosomes. c.239G>A was initially reported in the literature in three male and five female individuals in a study of patients undergoing testing for Fabry disease at a commercial laboratory (Lukas_2016). It was described as a mild variant shown to have reduced alpha-Gal-A enzyme activity (29.3% of normal) in transfected cells and was associated with slightly elevated biomarker (lyso-Gb3) values in those with the variant. Subsequently, this variant has also been reported in one case of sudden unexplained death associated with cardiac disease (Lin_2017), an Argentinian male dialysis patient with non-confirmed Fabry disease (Frabasil_2019), one unpublished case report of a patient with autism and learning diffculties but not clinically diagnosed with Fabry disease (Gupta_2019), in several unaffected Eucadorian Hispanic infants in a NY pilot NBS program who were not diagnosed with and had no family history of Fabry disease (Wasserstein_2019), and in a male individual given a clinical diagnosis of late onset Fabry disease (Delarosa-Rodriguez_2021). Several of these studies and and an internal case report that the variant is associated with reduced alpha-Gal-A activity and/or isolated leukocytes (Frabasil_2019, Wasserstein_2019, Gupta_2019, Delarosa-Rodriguez_2021, Internal data). The following publications have been ascertained in the context of this evaluation (PMID: 33527381, 31392112, 29247119, 26415523, 30093709). ClinVar contains an entry for this variant (Variation ID: 217380). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

GLA p.Gly80Asp (c.239G>A) is a missense variant that changes the amino acid at residue 80 from Glycine to Aspartic acid. This variant has been observed in at least one proband affected with Fabry disease (PMID:26415523;33527381). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:31392112;33527381;26415523;30093709). 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 p.Gly80Asp (c.239G>A) as a variant of unknown significance.

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to 29.3% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in three individuals referred for Fabry disease genetic testing (PMID: 26415523), one individual affected with sudden unexplained death (PMID: 29247119), eight unrelated newborns without a family history of Fabry disease (PMID: 30093709), one individual undergoing dialysis but not diagnosed with Fabry disease (PMID: 31392112), as well as in an individual affected with late-onset Fabry disease with renal symptoms (PMID: 33527381). Most of these carriers were males who usually showed high residual GLA enzyme activity and slightly elevated globotriaosylsphingosine (lyso-Gb3) levels (PMID: 26415523, 30093709, 31392112, 33527381). This variant has not been identified 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.

not provided Uncertain:4

Mar 29, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLA: PM2

Jun 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a likely pathogenic variant in a male with proteinuria, renal insufficiency decreased GLA activity and slight increase in lyso-Gb3 (PMID: 33527381); Classified as a benign variant after being identified through newborn screening in eight unaffected individuals; hemizygous males had GLA activity in leukocytes well above the affected range (PMID: 30093709); Identified in one male of a cohort of individuals with sudden unexplained death (PMID: 29247119); Identified in a cohort of male patients undergoing dialysis; this patient had decreased GLA activity but normal lyso-Gb3 and was not a confirmed Fabry disease case (PMID: 31392112); Published functional studies demonstrate this variant reduced GLA enzyme activity to 29% compared to wildtype (PMID: 26415523); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29961767, 38047356, PablosNG2023[Abstract], 29247119, 30093709, 26415523, 33527381, 31392112)

Cardiovascular phenotype Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.239G>A (p.G80D) alteration is located in coding exon 2 of the GLA gene. This alteration results from a G to A substitution at nucleotide position 239, causing the glycine (G) at amino acid position 80 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in individuals of Fabry disease cohorts, a renal failure cohort, and a sudden unexplained death cohort; however, clinical details were limited in some cases (Lukas, 2016; Lin, 2017; Frabasil, 2019; Wasserstein, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro enzyme analysis showed mild reduction in enzyme activity (Lukas, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Migalastat response Other:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
CardioboostCm	Uncertain	0.63
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.91		Gain of helix (P = 0.0696)
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=3/97	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: rs781838005; hg19: chrX-100658929;