rs797044776

chrX-101398012-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 5 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.789

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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398011-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222141.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=11, Likely_pathogenic=1}.
• 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	UniProt
GLA	NM_000169.3	c.1087C>T	p.Arg363Cys	missense_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2555G>A		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183376 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67824

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: 10 AN: 1096045 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 361427

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.: 23

Alfa AF: 0.000223 Hom.: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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	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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
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). -

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	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Pathogenic	0.85	D;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.6	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs797044776; hg19: chrX-100653000;