rs1555987215

chrX-101407877-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000169.3(GLA):c.26del(p.His9LeufsTer112) 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:4
• Conservation: PhyloP100: -1.41

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 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 458 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101407877-AT-A is Pathogenic according to our data. Variant chrX-101407877-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 523927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407877-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.26del	p.His9LeufsTer112	frameshift_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4058del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.26del	p.His9LeufsTer112	frameshift_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2021	Variant summary: GLA c.26delA (p.His9LeufsX112) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183413 control chromosomes. c.26delA has been reported in the literature in individuals affected with Fabry Disease (Eng_2001, Rosenberg_2000, Wang_2007, Gupta_2005). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2018	This variant has been reported in individuals affected with classical Fabry disease and in one unaffected carrier female (PMID: 10916280, 15712228). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His9Leufs*112) in the GLA gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

The c.26delA variant in the GLA gene has been reported previously in association with Fabry disease using alternate nomenclature (Eng et al., 1994). The deletion causes a frameshift starting with codon Histidine 9, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 112 of the new reading frame, denoted p.His9LeufsX112. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.26delA variant is not observed in large population cohorts (Lek et al., 2016). In summary, we interpret this variant as pathogenic. -

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: rs1555987215; hg19: chrX-100662865;