rs727505292

Variant names:

• chrX-101398828-A-G
• rs727505292
• NM_000169.3:c.758T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000169.3(GLA):​c.758T>C​(p.Ile253Thr) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I253S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 9.32
• Publications: 23 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 16 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, 15 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-101398828-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4087496.Status of the report is criteria_provided_single_submitter, 1 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, 0.821
• PP5: Variant X-101398828-A-G is Pathogenic according to our data. Variant chrX-101398828-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 180021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.758T>C	p.Ile253Thr	missense_variant	Exon 5 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.758T>C	p.Ile253Thr	missense_variant	Exon 5 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3371A>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:4

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 253 of the GLA protein (p.Ile253Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 23465405, 27896103, 34266644; Invitae). ClinVar contains an entry for this variant (Variation ID: 180021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 27657681). This variant disrupts the p.Ile253 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 23935525, 27657681), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.758T>C is a missense variant that changes the amino acid at residue 253 from Isoleucine to Threonine. This variant has been observed in at least one proband affected with Fabry disease (PMID:31242288;32915382;27657681;26415523;32023956;20071180;30386727;23332617;27896103;32150461;32442237;35743707;32432376;38002959). The variant was found to segregate with disease in at least one affected family (PMID:23332617;35743707;32432376;38002959). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:26415523;32023956;30723321;27657681). 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.758T>C as a likely pathogenic variant.

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:2

Sep 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 30477121, 32150461, 26712400, 26415523, 34266644, 27896103, 23465405, 27657681)

Apr 12, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The Ile253Thr variant in GLA has been reported in 1 male with Fabry disease (Sco tt 2013). It was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ile253Thr va riant is uncertain.

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
CardioboostCm	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		9.3
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;.
Vest4		0.96
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.97
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs727505292; hg19: chrX-100653816;