rs797044497

Variant names:

• chrX-101398076-T-G
• rs797044497
• NM_000169.3:c.1023A>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.1023A>C​(p.Glu341Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E341K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.508
• Publications: 10 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 19 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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-101398078-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.942
• PP5: Variant X-101398076-T-G is Pathogenic according to our data. Variant chrX-101398076-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 167136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1023A>C	p.Glu341Asp	missense	Exon 7 of 7	NP_000160.1
	GLA	NM_001406747.1		c.1146A>C	p.Glu382Asp	missense	Exon 8 of 8	NP_001393676.1
	GLA	NR_164783.1		n.1102A>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1023A>C	p.Glu341Asp	missense	Exon 7 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2619T>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1146A>C	p.Glu382Asp	missense	Exon 8 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000851 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 23, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fabry disease Pathogenic:1

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.1023A>C is a missense variant that changes the amino acid at residue 341 from Glutamic acid to Aspartic acid. This variant has been observed in at least one proband affected with Fabry disease (PMID:32023956;27657681;12175777). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;27657681;22004918). 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.1023A>C as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.51
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.70
Sift	Benign	0.49	T
Sift4G	Benign	0.56	T
Polyphen		0.79	P
Vest4		0.86
MutPred		0.84		Gain of loop (P = 0.2754)
MVP		1.0
MPC		1.3
ClinPred		0.96	D
GERP RS		0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.95
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs797044497; hg19: chrX-100653064;