X-101398012-G-A

Position:

chrX-101398012-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000169.3(GLA):c.1087C>T(p.Arg363Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000912 in 1,096,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 5 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.789

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant X-101398012-G-A is Pathogenic according to our data. Variant chrX-101398012-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398012-G-A is described in Lovd as [Pathogenic]. Variant chrX-101398012-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.1087C>T	p.Arg363Cys	missense_variant	7/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+2555G>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.1087C>T	p.Arg363Cys	missense_variant	7/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183376

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000912

AC:

AN:

1096045

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361427

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000223

Hom.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 09, 2021	This missense variant replaces arginine with cysteine at codon 363 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to 7.5% residual GLA enzyme activity when expressed in HEK-293 cells (PMID: 21598360). This variant has been reported in individuals affected with Fabry disease (PMID: 12175777, 19387866, 28749998, 29661900, 32442237) and a female with left ventricular hypertrophy (PMID: 31987665). Cultured cells from an affected male showed 8% residual GLA enzyme activity (PMID: 19387866), and an affected female showed elevated lysoglobotriaosylceramide levels (PMID: 28749998). This variant has been reported in a newborn (PMID: 28615118) and in a 33-year-old asymptomatic female (PMID: 31117083). Both of them had reduced GLA enzyme activity. This variant has been identified in 2/183376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg363His, has been associated with Fabry disease (Clinvar variation ID: 222141), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2022	Variant summary: GLA c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183376 control chromosomes (gnomAD). c.1087C>T has been reported in the literature in individuals affected with later onset or non-classic presentations of Fabry Disease (example, Balendran_2020, Mauhin_2020, Arends_2018) and as a variant causing classical Fabry disease (example, Shabbeer_2002, cited in Benjamin_2009). These data do not allow a firm conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (example, Wu_2011, Benjamin_2009). The most pronounced variant effect results in <10% of normal activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 27, 2019	GLA Arg353Cys has been previously identified in 5 Fabry patients (Phyu P, et al., 2018; Pettazzoni M, et al., 2017; Benjamin ER, et al., 2009; Shabbeer J, et al., 2002). We identified this variant in a patient presenting with left ventricular hypertrophy, subsequent clinical screening confirmed a diagnosis of Fabry disease. The variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.000011 http://gnomad.broadinstitute.org/). In silico tools SIFT and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "Disease causing". Interestingly another amino acid change at this position (Arg363His) has been classified as pathogenic. suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on rarity in the general population, reports of this variant in affected individuals, and because Fabry disease is caused only by variants in the GLA gene, we classify GLA Arg353Cys as "likely pathogenic". -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg363Cys variant in GLA has been reported in the literature in two males with classic Fabry, as well as in five individuals in ClinVar (PMID: 12175777, 21598360; ID:198401), and has been identified in 0.00244% (2/81841) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044776). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as pathogenic by EGL Genetic Diagnostics (VariationID:198401). In vitro functional studies provide some evidence that the p.Arg363Cys variant may slightly impact protein function (PMID: 21598360, 27744182, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype that is consistent with disease (PMID: 12175777). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Arg363His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 28302345,12175777, 23935525, 26937405,11668641,25382311/Variation ID: 222141). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PS4_moderate, PP4, PM5_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the GLA protein (p.Arg363Cys). This variant is present in population databases (rs797044776, gnomAD 0.002%). This missense change has been observed in individual(s) with features of Fabry disease (PMID: 12175777; Invitae). ClinVar contains an entry for this variant (Variation ID: 198401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668641, 12175777, 26937405, 28302345). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2023	Published functional studies demonstrate significantly reduced enzyme activity (Wu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29437868, 31860127, 25382311, 22063097, 28615118, 12175777, 27657681, 32442237, 31987665, 21598360) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 15, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

CardioboostCm

Benign

0.012

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.85

D;.

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.6

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.5

D;.

REVEL

Uncertain

0.53

Sift

Benign

0.17

T;.

Sift4G

Benign

0.17

T;.

Polyphen

0.62

P;.

Vest4

0.26

MutPred

0.89

Gain of catalytic residue at P362 (P = 0.023);.;

MVP

0.96

MPC

1.0

ClinPred

0.41

GERP RS

0.97

Varity_R

0.45

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over