X-101398906-C-T

Position:

• chrX-101398906-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.680G>A​(p.Arg227Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.84

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]

GLA (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-101398906-C-T is Pathogenic according to our data. Variant chrX-101398906-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398906-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.680G>A	p.Arg227Gln	missense_variant	5/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.680G>A	p.Arg227Gln	missense_variant	5/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3449C>T		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2020	Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in 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 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	This missense variant replaces arginine with glutamine at codon 227 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. In vitro functional studies using transfected HEK-293 cells as well as patient-derived cell lines have shown that this variant causes a significant reduction in GLA enzyme activity (PMID: 18698230, 21598360, 23935525, 32023956). This variant has been reported in at least nine males and eight females affected with Fabry disease (PMID: 10916280, 12920095, 15713906, 28283366, 29132836, 29950951, 30738278, 32813676, 33204599, 33807900, 34877240, 36140787). It has been shown that this variant segregates with disease in multiple affected individuals, both male and female, in one large family (PMID: 20615758). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 28, 2023	PP3, PP4, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2024	The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	5.0	H;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.97		Loss of MoRF binding (P = 0.0795);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs104894840; hg19: chrX-100653894;