rs886044829

chrX-101398040-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000169.3(GLA):c.1057_1058del(p.Met353AspfsTer21) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.85

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:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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 55 pathogenic variants in the truncated region.
• PP5: Variant X-101398040-CAT-C is Pathogenic according to our data. Variant chrX-101398040-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398040-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.1057_1058del	p.Met353AspfsTer21	frameshift_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2585_300+2586del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.1057_1058del	p.Met353AspfsTer21	frameshift_variant	7/7	1	NM_000169.3	P1

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2016	Variant summary: The GLA c.1057_1058delAT (p.Met353Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in one affected individual via a publication. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Probable Disease Variant/Likely Pathogenic," until additional information becomes available. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 24, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GLA protein. Other variant(s) that disrupt this region (p.Tyr397Metfs*7) have been determined to be pathogenic (PMID: 10666480). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with Fabry disease (PMID: 9100224). ClinVar contains an entry for this variant (Variation ID: 284485). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met353Aspfs*21) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the GLA protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 30, 2015

- -

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: rs886044829; hg19: chrX-100653028;