rs869312316

Variant names:

• chrX-101407849-GGAAGC-G
• rs869312316
• NM_000169.3:c.50_54delGCTTC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000169.3(GLA):​c.50_54delGCTTC​(p.Arg17ProfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.77
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1093 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101407849-GGAAGC-G is Pathogenic according to our data. Variant chrX-101407849-GGAAGC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 222273.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.50_54delGCTTC	p.Arg17ProfsTer12	frameshift	Exon 1 of 7	NP_000160.1
	GLA	NM_001406747.1		c.50_54delGCTTC	p.Arg17ProfsTer12	frameshift	Exon 1 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.50_54delGCTTC	p.Arg17ProfsTer12	frameshift	Exon 1 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.50_54delGCTTC	p.Arg17ProfsTer12	frameshift	Exon 1 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4080_301-4076delAAGCG		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.50_54delGCTTC	p.Arg17ProfsTer12	frameshift	Exon 1 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:2

Sep 15, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA p.Arg17ProfsTer12 (c.50_54del) is a frameshift variant that results in the production of a truncated protein that may be subject to nonsense-mediated mRNA decay. This variant has been observed in at least one proband affected with Fabry disease (PMID: 39620496). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify GLA p.Arg17ProfsTer12 (c.50_54del) as a pathogenic variant.

Mar 06, 2017

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. While this particular variant has not been reported in the literature, loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This sequence change deletes 5 nucleotides from exon 1 of the GLA mRNA (c.50_54delGCTTC), causing a frameshift at codon 17. This creates a premature translational stop signal (p.Arg17Profs*12) and is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869312316; hg19: chrX-100662837;