X-101403941-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 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).

• 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:2 U:11 O:1
• Conservation: PhyloP100: 7.90

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.239G>A	p.Gly80Asp	missense_variant	Exon 2 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.239G>A	p.Gly80Asp	missense_variant	Exon 2 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-7995C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112527 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34697

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000941

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:2 Uncertain:5

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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. -

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. -

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) -

not specified Uncertain:1

Jul 13, 2023

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

Significance: Uncertain significance

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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183388 control chromosomes (gnomAD). 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 report that the variant is associated with reduced alpha-Gal-A activity in plasma and/or isolated leukocytes (Frabasil_2019, Wasserstein_2019, Gupta_2019, Delarosa-Rodriguez_2021), however it also has a fairly high frequency reported in the admixed American population (Wasserstein_2019). Therefore, it is currently unclear whether this reduced, but significant residual level of activity associated with the variant is either insufficient to manifest as a clinical phenotype or is instead likely to result in the late onset form of the disease. The following publications have been ascertained in the context of this evaluation (PMID: 33527381, 31392112, 29247119, 26415523, 30093709). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either VUS (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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 v4.3

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;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	H;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs781838005; hg19: chrX-100658929;