Variant X-101398064-TGA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000169.3(GLA):c.1033_1034del(p.Ser345ArgfsTer29) variant causes a frameshift change. 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.50

Variant links:

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]

GLA links:

RPL36A-HNRNPH2 (HGNC:):

RPL36A-HNRNPH2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-101398064-TGA-T is Pathogenic according to our data. Variant chrX-101398064-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 92538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398064-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.1033_1034del	p.Ser345ArgfsTer29	frameshift_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+2613_300+2614del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.1033_1034del	p.Ser345ArgfsTer29	frameshift_variant	7/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2016	Variant summary: The GLA c.1033_1034delTC (p.Ser345Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87610 control chromosomes while it was reported in several Fabry patients indicating pathogenicity. GLA activity, GLA protein levels were severely decreased in affected carriers with Lyso-Gb3 being elevated further supporting pathogenicity. Additionally, a clinical diagnostic laboratory classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Ser345Argfs29) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the GLA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Fabry disease (PMID: 8931708, 23935525). This variant is also known as L344-X28-Stop and c.1029-1030delTC. ClinVar contains an entry for this variant (Variation ID: 92538). This variant disrupts a region of the GLA protein in which other variant(s) (p.Val376Profs10) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2015	The c.1033_1034delTC mutation in the GLA gene has been reported previously in several unrelated males with Fabry disease and significantly reduced a-galactosidase activity (Germain et al., 1996; Pereira et al., 2007; Tsukimura et al., 2014). The deletion causes a frameshift starting with codon Serine 345, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Ser345ArgfsX29. This mutation is predicted to cause loss of normal protein function through protein truncation. This result is expected to be consistent with a diagnosis of Fabry disease -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing