rs111422676

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting

The NM_000169.3(GLA):c.1088G>A(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,207,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 9 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:2

Conservation

PhyloP100: -0.0720

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: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]

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant X-101398011-C-T is Pathogenic according to our data. Variant chrX-101398011-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398011-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000125 (14/111964) while in subpopulation AMR AF= 0.00133 (14/10556). AF 95% confidence interval is 0.000802. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.1088G>A	p.Arg363His	missense_variant	Exon 7 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.1088G>A	p.Arg363His	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+2554C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111964

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

34152

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000545

AC:

AN:

183364

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

67812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1096001

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361377

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000125

AC:

AN:

111964

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

34152

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:12Uncertain:1

Sep 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R363H in GLA (NM_000169.2) has been reported previously in affected individuals with late onset Fabry disease (Blaydon et al 2001; Serebrinsky et al, 2015). In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015). I t has been classified as a Pathogenic for the late onset phenotype by the Fabry disease working group (Germain et al,2 020). It has been submitted to ClinVar with conflicting interpretations including VUS/Likely Pathogenic and Pathogenic. It is present in 6 hemizygous males in the gnomAD database. However presence of clinical variability ranging from single organ involvement to ascertainment via family screening could account for the presence of these hemizygous males within the gnomAD database. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated and the residue is weakly conserved across species. For these reasons, this variant has been classified as Pathogenic -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 363 of the GLA protein (p.Arg363His). This variant is present in population databases (rs111422676, gnomAD 0.03%). This missense change has been observed in individual(s) with Fabry disease (PMID: 11668641, 12175777, 26937405, 28302345). ClinVar contains an entry for this variant (Variation ID: 222141). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 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: 12175777, 21598360, 25835592, 26937405; internal data). 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. -

Nov 20, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg363His variant in GLA has been reported in at least eight individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345), segregated with disease in three affected relatives from one family (PMID: 26937405), and has been identified in 0.03% (5/19142) of South Asian chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111422676). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Additionally, this variant has a high prevalence in late-onset cases, which may account for the frequency in gnomAD. This variant has also been reported in ClinVar as Pathogenic by EGL Genetic Diagnostics and Integrated Genetics (Variation ID: 222141). In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 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 individuals hemizygous for this variant is highly specific for Fabry disease based on enzymatic diagnosis consistent with disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic despite the higher than expected allele frequency in the general population. ACMG/AMP Criteria applied: BS1_supporting, PP1_moderate, PP4, PS3_supporting, PS4_moderate (Richards 2015). -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/88023 control chromosomes (3 hemizygotes) at a frequency of 0.0000341, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant has been reported in multiple patients with classic or late-onset Fabry disease. In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.R363C and p.R363P have been reported to associate with Fabry disease, suggesting R363 is critical for GLA function. Taken together, this variant is classified as pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 363 of the GLA protein. Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro, with a greater than 70% decrease compared to wild type (PMID: 21598360, 23935525). This variant has been reported in four individuals affected with classic Fabry disease and in more than 10 individuals affected with late-onset or non-classical Fabry disease (PMID: 11668641, 12175777, 21420783, 26937405, 28360401, 30477121, 33022387, 33163363, 33204599, 33437642, 34545322, 36624527). In all tested carrier individuals, decreased leukocyte GLA enzyme activities and increased plasma biomarker globotriaosylsphingosine (lyso-Gb3) levels were observed (PMID: 19387866, 21420783, 28302345, 33022387, 34199132). This variant has been identified in 10/183364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant affecting the same codon, p.Arg363Cys, is considered to be disease-causing (ClinVar variation ID: 198401), suggesting that arginine at this position is important for GLA protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1088G>A (p.Arg363His) variant in the GLA gene is located in the exon 7 of the GLA gene and is predicted to replace arginine with histidine at codon 363 of the GLA protein. This variant has been identified in many individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 28360401, 28302345, 36624527, 34545322, 33437642, 33163363), and reported as segregated with disease in three affected relatives from one family (PMID: 26937405). This variant has been reported to be associated with a later-onset and milder course of disease in males (PMID 26937405, 32161151, 32418857). Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID: 19387866, 21598360, respectively). This variant is rare in the general population according to gnomAD v4.0.0 (0.002%). A different variant affecting the same amino acid residue Arg363 (c.1087C>T, p.Arg363Cys) has been determined to be pathogenic in ClinVar according to ACMG guidelines. Therefore, the c.1088G>A (p.Arg363His) variant in the GLA gene has been classified as pathogenic. -

not provided

Pathogenic:2Uncertain:1

Apr 27, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

May 01, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Dec 24, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1088G>A (p.R363H) alteration is located in exon 7 (coding exon 7) of the GLA gene. This alteration results from a G to A substitution at nucleotide position 1088, causing the arginine (R) at amino acid position 363 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.005454% (10/183364) total alleles studied, with 6 hemizygote(s) observed. The highest observed frequency was 0.02621% (5/19078) of South Asian alleles. This variant was identified in one or more individuals with features consistent with Fabry disease, often with late onset and/or a renal presentation (Germain, 2020; Politei, 2021; Zenone, 2011; Harale, 2024; external communication), and segregated with disease in at least one family (Serebrinsky, 2015; Delarosa-Rodríguez, 2021). This amino acid position is not well conserved in available vertebrate species. In multiple assays testing GLA function, this variant showed functionally indeterminant results (Lukas, 2013; Wu, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

CardioboostCm

Benign

0.023

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Uncertain

0.67

D;.

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Pathogenic

2.0

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;.

REVEL

Uncertain

0.44

Sift

Benign

0.47

T;.

Sift4G

Benign

0.51

T;.

Polyphen

0.41

B;.

Vest4

0.64

MutPred

0.86

Loss of sheet (P = 0.0817);.;

MVP

0.98

MPC

0.90

ClinPred

0.019

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.79

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