X-101398856-C-T

Variant names:

• chrX-101398856-C-T
• rs727503948
• NM_000169.3:c.730G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000169.3(GLA):​c.730G>A​(p.Asp244Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D244H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.04
• Publications: 20 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 10 ACMG points.

• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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-101398856-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562436.
• 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, 0.858
• PP5: Variant X-101398856-C-T is Pathogenic according to our data. Variant chrX-101398856-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167139.

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.730G>A	p.Asp244Asn	missense	Exon 5 of 7	NP_000160.1
	GLA	NM_001406747.1		c.853G>A	p.Asp285Asn	missense	Exon 6 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.730G>A	p.Asp244Asn	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.730G>A	p.Asp244Asn	missense	Exon 5 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3399C>T		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.853G>A	p.Asp285Asn	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:1 Uncertain:1

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.730G>A is a missense variant that changes the amino acid at residue 244 from Aspartic acid to Asparagine. This variant has been observed in at least one proband affected with Fabry disease (PMID:15091117;30723321;36406818;30972193;7531540;27083555;23332617;27657681;31242288;33437642). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:30723321;22773828;27657681;21890869;27083555;28069318). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify GLA c.730G>A as a variant of unknown significance.

Jun 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 21598360, 22773828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 167139). This missense change has been observed in individuals with Fabry disease (PMID: 7531540, 15091117, 33437642). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 244 of the GLA protein (p.Asp244Asn).

not provided Pathogenic:1

Mar 06, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
CardioboostCm	Uncertain	0.15
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.47
Sift	Benign	0.16	T
Sift4G	Benign	0.12	T
Polyphen		0.17	B
Vest4		0.49
MutPred		0.87		Gain of MoRF binding (P = 0.0627)
MVP		0.97
MPC		0.99
ClinPred		0.73	D
GERP RS		5.1
Varity_R		0.63
gMVP		0.95
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727503948; hg19: chrX-100653844;