rs148158093

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_000169.3(GLA):c.352C>T(p.Arg118Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,209,304 control chromosomes in the GnomAD database, including 2 homozygotes. There are 219 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., 13 hem., cov: 23)

Exomes 𝑓: 0.00063 ( 1 hom. 206 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:18B:3O:1

Conservation

PhyloP100: 2.23

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000169.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

BS2

High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.352C>T	p.Arg118Cys	missense_variant	2/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.301-8108G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.352C>T	p.Arg118Cys	missense_variant	2/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000400

AC:

AN:

112545

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

AN XY:

34711

show subpopulations

Gnomad AFR

AF:

0.0000646

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000564

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000224

AC:

AN:

183291

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

67751

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000109

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:

0.000428

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000626

AC:

687

AN:

1096759

Hom.:

Cov.:

AF XY:

0.000569

AC XY:

206

AN XY:

362157

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000170

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:

0.000770

Gnomad4 OTH exome

AF:

0.000586

GnomAD4 genome

AF:

0.000400

AC:

AN:

112545

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

AN XY:

34711

show subpopulations

Gnomad4 AFR

AF:

0.0000646

Gnomad4 AMR

AF:

0.000564

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000602

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:18Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:10Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 09, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5,BP6. This variant was detected in hemizygous state. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces arginine with cysteine at codon 118 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). Functional studies have shown that this variant causes partially reduced GLA enzyme activity in mammalian cells (PMID: 23935525, 16773563). This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 20122163, 22551898, 25468652, 35743707) and with hypertrophic cardiomyopathy (PMID: 31291414, 32531501, Koraichi et al. 2021, DOI: 10.1016/j.acvdsp.2020.10.086). A study of 22 individuals of Portuguese and Spanish ancestry carrying this variant, including 3 homozygous females, has suggested that this variant does not appear to segregate with Fabry disease (PMID: 25468652). This variant has been observed in an individual affected with idiopathic end-stage renal failure (PMID: 31566927). His three sons and two daughters who carried this variant were asymptomatic with normal GLA enzyme activity. This variant has been identified in 48/205229 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and includes 17 hemizygous observations. In summary, while this variant has been reported in individuals affected with GLA-related disorders, the role of this variant in disease cannot be determined conclusively due to the frequent variant observation in unaffected individuals. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Curated 19/3/2021: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS - 3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Truncating variants in the last exon have been reported with a dominant negative mechanism, while those predicted to undergo nonsense mediated decay been reported with a loss of function mechanism. Missense variants have been reported with both aforementioned mechanisms. Gain of function has also been suggested, however more evidence is required (PMID: 8878432; PMID: 31613176). (I) 0109 - This gene is associated with X-linked disease. Both males and females have been reported with Fabry disease, though the latter are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (30 heterozygotes, 1 homozygote, 13 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated melibiase 2 domain (Pfam). (I) 0701 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg118His) has previously been reported as a VUS in at least one publication (PMID 30477121). Alternative amino acid changes to serine, glycine, proline and leucine have not been reported in patients, however, were studied via site-directed mutagenesis and found to result in enzymatic activities ranging from 40-70% of wild-type, which is higher that 20% found for p.(Arg118Cys) (PMID: 23935525). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a variant of uncertain significance (11x) and likely pathogenic (2x) in ClinVar. In the literature, it has been reported in both male and female patients, where the variant results in residual enzyme activities that is consistent with mild, late onset Fabry disease (PMID: 16773563; 20122163; 30569317; 31291414). However, the pathogenicity of this variant has been called into question by at least one publication by demonstrating that the variant does not segregate with Fabry disease (PMID: 25468652) and in another publication where a different variant in GLA was deemed to be causative of FD the family (PMID:28941980). Lukas et al (2013) refer to this variant's clinical phenotype as being a "variant phenotype" (PMID: 23935525). The "variant phenotype" is explained by Andrade et al (2008) as having a low level of residual alpha-galactosidase activity that protects patients from developing classic FD, however some patients may present with late onset end-organ failure (PMID: 18003767). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Gaspar et al (2010) measured alpha-galactose activity in patient leukocytes and found that the variant conferred a reduction of enzyme activity to 35% of wild-type in 1 hemizygous male and 60%-79% of wild-type in 2 heterozygous females (PMID: 20122163). In vitro functional studies of this variant showed a reduction of enzymatic actiivities ranging between 20-29% in 2 independent studies (PMID: 1677356; 23935525). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg118Cys variant in GLA has been reported in at least 11 individuals with Fabry disease (PMID: 28596458, 16773563, 20122163, 21890869, 22551898, 28299312, 28409012, 21946453, 20110537, 25468652, 24582695, 24661928, 18830871), and has been identified in 0.044% (41/92573) of European (non-Finnish) chromosomes, including 16 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148158093). This variant has also been reported in ClinVar as a VUS by the Laboratory for Molecular Medicine, GeneDx, Invitae, Ambry Genetics, GeneReviews, and the University of Washington Medical Center and as likely pathogenic by EGL Genetic Diagnostics (Variation ID: 42454). In vitro functional studies provide some evidence that the p.Arg118Cys variant may impact protein function (PMID: 23935525, 28646478, 16773563, 25468652, 20122163). 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 consistent with the disease (PMID: 28596458, 16773563, 20122163, 21890869, 22551898, 28299312, 28409012, 21946453, 20110537, 25468652, 24582695, 24661928, 18830871). This variant was found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 28941980) In summary, the clinical significance of the p.Arg118Cys variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: BS1, PS3_moderate, PP4, BP2 (Richards 2015). -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in a female patient having exome sequencing for an unrelated indication. No known history of Fabry disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 118 of the GLA protein (p.Arg118Cys). This variant is present in population databases (rs148158093, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with mild, atypical or late-onset Fabry disease (PMID: 16773563, 18830871, 20110537, 20122163, 21890869, 22551898, 25179549, 25468652, 29631605, 30569317, 30773290). ClinVar contains an entry for this variant (Variation ID: 42454). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 23935525). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 18, 2022	- -

not provided

Pathogenic:1Uncertain:3Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2023	- -
Likely benign, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	GLA: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2023	See Variant Classification Assertion Criteria. -
Likely pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 26, 2017	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Arg118Cys variant in GLA has been reported in 11 individuals with classic or late-onset Fabry disease and segregated with disease in at least 2 affected family members. This variant has also been identified in at least 2 individuals with reduced a-galactosidase activity, 6 individuals who had stroke, 1 individual who had MI, 1 individual with small fiber neuropathy, 1 individual with juvenile idiopathic arthritis, 4 individuals with LVH, 1 child with HCM, 2 infants with RCM and DCM, and 3 individuals with other phenotypes (Spada 2006, Gaspar 2010, Baptista 2010, Kiesling 2014, Genoni 2011, Morais 2008, Elliott 2011, Turaca 2012, Caetano 2014, Pasqualim 2014, Colon 2017, Barajas-Colon 2017, de Greef 2016, Goncalves 2017, Kilarski 2015, Schiffmann 2017, Samuelsson 2014, Ferreira 2015). However, this variant has also been reported in 7 asymptomatic family members, including 3 homozygous females, (Ferreira 2015) and did not segregate with cardiac phenotypes in 3 affected family members of 2 different families (Golbus 2014, LMM data). This variant has been reported in ClinVar (Variation ID 42454) and has been identified in 36/90523 of European chromosomes, including 14 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148158093). GLA activity in individuals carrying this variant was reduced, but did not reach levels associated with classic Fabry disease. Similarly, in vitro functional studies showed enzyme activity of 20-29% (Spada 2006, Lukas 2013). Computational prediction tools and conservation analysis suggest that the p.Arg118Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg118Cys variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS4_M; PVS1_Moderate; PP1; PP3; BS4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2023	Variant summary: GLA c.352C>T (p.Arg118Cys) results in a non-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 allele was found at a frequency of 0.00023 in 184752 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GLA causing Fabry Disease (0.00023 vs 0.005). However, the finding of 17 hemizygous occurrences in gnomAD may be evidence against pathogenicity, although the possibility of reduced penetrance and/or subclinical cases cannot be ruled out. This variant has been found in patients predominantly of Portuguese or Spanish ancestry, with clinical features ranging from no symptoms to acute cerebrovascular disease, ischemic stroke, intracerebral hemorrhage, cerebral venous thrombosis, kidney diseases, dilated cardiomyopathy, and hypertrophic cardiomyopathy (e.g. Morais_2008, Baptista_2010, Gaspar_2010, Valbuena_2012, Rolfs _2013, Caetano_2014, Golbus_2014, Alharbi_2019, Varela_2020, Delarosa-Rodriguez_2021). In patients (harboring this variant) who presented with cardiological manifestations that are shared by Fabry disease (FD) as well as other independent cardiac phenotypes (such as DCM), a deleterious variant was also found (TPM1 D230N; Golbus_2014). Additionally, this variant has been reported in patients who did not meet clinical criteria for FD (e.g. Morais_2008, Kilarski_2015, de Greef_2016, Nowak_2019, Azevedo_2020, Stiles_2020). Furthermore, Ferreira et al (2015) reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the R118C allele and concluded that the variant did not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. Additionally, co-occurrence of the variant in cis with a pathogenic variant (GLA deletion of exons 3 and 4) was reported in a multi-generational family affected with Fabry Disease, providing supporting evidence for a benign role (Barbeito-Caamano_2018). Although in vitro studies strongly suggest decreased enzymatic activity associated with this variant (Lukas_2013, Spada_2006), enzymatic evaluation in patients' blood or plasma varied from reduced enzymatic level to normal levels. Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority of submitters classified the variant as VUS (n=17), and others classified it as either likely pathogenic (n=2) or likely benign (n=2). Taken together, this variant is classified as VUS until more definitive data on genotype-phenotype associations and disease progression/natural history and burden become available. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 22, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 15, 2019	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.352C>T (p.R118C) alteration is located in exon 2 (coding exon 2) of the GLA gene. This alteration results from a C to T substitution at nucleotide position 352, causing the arginine (R) at amino acid position 118 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Uncertain

0.12

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Pathogenic

0.31

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

D;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

0.65

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

0.99

D;.

Vest4

0.23

MVP

0.99

MPC

1.7

ClinPred

0.84

GERP RS

3.9

Varity_R

0.55

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