rs730880453

Variant names:

• chrX-101398024-TCTC-T
• rs730880453
• NM_000169.3:c.1072_1074delGAG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000169.3(GLA):​c.1072_1074delGAG​(p.Glu358del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.37

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

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000169.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-101398024-TCTC-T is Pathogenic according to our data. Variant chrX-101398024-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398024-TCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.1072_1074delGAG	p.Glu358del	conservative_inframe_deletion	Exon 7 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1072_1074delGAG	p.Glu358del	conservative_inframe_deletion	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2570_300+2572delCCT		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

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/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:4

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.1072_1074delGAG (p.Glu358del) results in an in-frame deletion that is predicted to remove a Glutamate amino acid from the C-terminal beta-sandwich domain (IPR035373) of the encoded protein. The variant was absent in 183351 control chromosomes (gnomAD). c.1072_1074delGAG has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Blanch_1996, Topaloglu_1999, Wu_2004, Schafer_2005, Monserrat_2007, Shin_2008, Sawada_2020, Hongo_2020). These data indicate that the variant is very likely to be associated with disease. These publications also reported alpha-galactosidase activity values, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals with Fabry disease (PMID: 8807334, 12175777, 15339079, 15713906, 18154966, 26297554, 30468909, 32161151, 34679477, 34356073, 38002959). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to result in an in-frame deletion that will affect a region critical to protein function. This prediction has not been confirmed by functional studies. -

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1072_1074del, results in the deletion of 1 amino acid(s) of the GLA protein (p.Glu358del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 8807334, 15339079, 15712228, 15713906, 18154965, 26297554). ClinVar contains an entry for this variant (Variation ID: 180844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Glu358 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452068, 12428061, 16595074, 21598360, 24386359, 25382311, 26297554, 26415523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18154965, 30116053, 30386727, 12428061, 12512750, 11804208, 15339079, 31956509, 31509825, 28340691, 26415523, 24386359, 21598360, 16595074, 15712228, 26297554, 10666480, 32714835, 32843101, 8807334, 27657681, 33437642, 18698230) -

Aug 14, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880453; hg19: chrX-100653012;