X-101398825-A-G

Variant names:

• chrX-101398825-A-G
• rs869312153
• NM_000169.3:c.761T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000169.3(GLA):​c.761T>C​(p.Val254Ala) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1 O:1
• Conservation: PhyloP100: 6.09
• Publications: 1 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 7 ACMG points.

• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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, 0.919

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.761T>C	p.Val254Ala	missense	Exon 5 of 7	NP_000160.1
	GLA	NM_001406747.1		c.884T>C	p.Val295Ala	missense	Exon 6 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.761T>C	p.Val254Ala	missense	Exon 5 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.761T>C	p.Val254Ala	missense	Exon 5 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3368A>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.884T>C	p.Val295Ala	missense	Exon 6 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Pathogenic:2 Uncertain:1

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.761T>C is a missense variant that changes the amino acid at residue 254 from Valine to Alanine. This variant has been observed in at least one proband affected with Fabry disease (PMID:26415523). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:26415523). 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.761T>C as a variant of unknown significance.

Aug 07, 2025

Nephrology Department, Antalya Training and Research Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GLA c.761T>C (p.Val254Ala) variant is a rare missense substitution located in exon 5 of the GLA gene. It replaces a highly conserved valine residue with alanine in a functionally important region of the α-galactosidase A enzyme. This variant has been reported only once previously in the literature as likely pathogenic, without detailed phenotypic description. In our cohort, it was identified in 19 related individuals, three of whom exhibited neurological manifestations such as recurrent stroke, sensory neuropathy, and characteristic white matter lesions on brain MRI, consistent with Fabry disease. Mild cardiac hypertrophy was observed in several carriers, while renal function remained preserved. The variant is absent from population databases (gnomAD, ExAC) and predicted to be deleterious by multiple in silico tools (PolyPhen-2, SIFT, CADD). Segregation analysis within the family supports association with disease, as all symptomatic individuals harbored the variant, and no unaffected males were positive. Although functional studies are lacking, the clinical phenotype, conservation of the residue, absence from controls, and segregation data collectively support a classification of “likely pathogenic” according to ACMG/AMP criteria (PM1, PM2, PP1, PP3). In summary, the c.761T>C (p.Val254Ala) variant appears to define a neurologically predominant form of Fabry disease with late-onset cerebrovascular involvement and minimal renal findings. Further accumulation of functional and international case data will be essential for definitive pathogenic confirmation

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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: yes

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
CardioboostCm	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.67	N
PhyloP100		6.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.76
Sift	Benign	0.50	T
Sift4G	Benign	0.60	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.77		Loss of helix (P = 0.1299)
MVP		1.0
MPC		1.9
ClinPred		0.84	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.96
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869312153; hg19: chrX-100653813;