rs28935493

chrX-101398074-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):c.1025G>A(p.Arg342Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 112,349 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R342G) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.50

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398075-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167135.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-101398074-C-T is Pathogenic according to our data. Variant chrX-101398074-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398074-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.1025G>A	p.Arg342Gln	missense_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2617C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.1025G>A	p.Arg342Gln	missense_variant	7/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112349 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34507

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112349 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34507

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 342 of the GLA protein (p.Arg342Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 8012363, 24626659). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10742). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 15, 2017	A hemizygous c.1025G>A (p.R342Q) pathogenic variant in the GLA gene was detected in this individual. This variant has been previously reported in patients with Fabry disease (PMID, 11531972, 18424138, 24626659, 2458695). Defects in GLA are the cause of Fabry disease [MIM:301500], an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. Studies characterizing the effect of the c.1025G>A (p.R342Q) on GLA function have shown impaired GLA activity (PMID, 21598360, 23935525). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2021	Variant summary: GLA c.1025G>A (p.Arg342Gln) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 178226 control chromosomes. c.1025G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example, Pasqualim_2014, Turaca_2012, Vedder_2008, Echevarria_2015, Hulkova_2010). These data indicate that the variant is very likely to be associated with disease. The variant has been shown to have significantly reduced GLA activity in both patients and in vitro studies (example, Vedder_2008, Wu_2011). Three 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	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.86		Gain of catalytic residue at R342 (P = 0.0039);.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28935493; hg19: chrX-100653062;