rs727503950

Positions:

chrX-101400712-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2

The NM_000169.3(GLA):c.593T>C(p.Ile198Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,192,707 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 4 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:5O:1

Conservation

PhyloP100: 9.30

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant X-101400712-A-G is Pathogenic according to our data. Variant chrX-101400712-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167142.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4, Pathogenic=2}.

BS2

High Hemizygotes in GnomAdExome4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.593T>C	p.Ile198Thr	missense_variant	4/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+5255A>G		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.593T>C	p.Ile198Thr	missense_variant	4/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112219

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34365

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181907

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

66423

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1080488

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

347666

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:

0.0000187

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000169

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112219

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34365

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:4Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces isoleucine with threonine at codon 198 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant may retain significant residual GLA enzyme activity in the range of 35%-60% compared to the wild type (PMID: 26415523, 31036492). This variant has been reported in individuals affected with Fabry disease (PMID: 21587323, 25511234, 25974833). It has also been reported in individuals with suspected diagnoses of Fabry disease (PMID: 25149322, 26415523, 31996269, 32802993). It has been shown that this variant segregates with disease in 5 affected individuals from one family (PMID: 21587323). This variant has been identified in 2/181907 chromosomes, including 1 hemizygote, in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ile198Thr variant in GLA has been reported in 2 males and 2 females with Fabry disease (PMID: 26415523, 25974833, 21587323), and has been identified in 0.0025% (2/81184) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727503950). 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 likely pathogenic by EGL Genetic Diagnostics and the Albrecht-Kossel-Institute, and as a VUS by Invitae (Variation ID: 167142). In vitro functional studies provide some evidence that the p.Ile198Thr variant may slightly impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant will impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based the on classical phenotype consistent with disease (PMID: 21587323, 25149322, 26415523). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS3_supporting, PS4_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the GLA protein (p.Ile198Thr). This variant is present in population databases (rs727503950, gnomAD 0.003%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21587323, 25149322, 25974833; Invitae). ClinVar contains an entry for this variant (Variation ID: 167142). 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: 26415523). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2022	Variant summary: GLA c.593T>C (p.Ile198Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 181907 control chromosomes (gnomAD). c.593T>C has been reported in the literature in (1). two individuals affected with later onset Fabry Disease, one of whom was reported as having no angiokeratoma but evidence of vascular disease (example, Germain_2014, Pettazzoni_2017), (2). in a 6.4 year old male with Fabry disease from a cohort of treated and untreated pediatric and adult Fabry patients (example, Auray-Blais_2015), (3). in a male patient characterized enzymatically as having a later onset Fabry disease (i.e., >20% WT activity levels) and a slight elevation in Lyso-Gb3 levels (example, Lukas_2016), (4). in a male with a suspected phenotype of later onset Fabry disease (Varela_2020), (5). in two heterozygous females affected with Fabry disease who displayed random X-chromosome inactivation and alpha galctodisease activity levels of 27 and 46% of WT (Echevarria_2016), and (6). in a 16 year old male kidney donor with reduced plasma Alpha-Galactosidase A activity (<10% of WT), large and constant amounts of Fabry-specific lipid deposits, mainly in podocytes from graft biopsy samples analyzed at transplantation and at 3 and 12 years of age, but no other indications of clinical disease (Houge_2011). Based on evaluation and analysis of the clinically unaffected mother and sisters, this patient reported by Houge_2011 was characterized by the authors as having a non-penetrant biochemically true positive but clinically false-positive allele. These data indicate that the variant is a mild and/or incompletely penetrant allele that is likely to be associated with disease. Multiple publications report conflicting experimental evidence evaluating an impact on protein function depending upon the specimen type and/or the in-vitro experimental system utilized (example, Houge_2011, Lukas_2016, Echevarria_2016, Oommen_2019). The most pronounced variant effect varies from <10% of normal alpha galactosidase activity in a male donor plasma specimen (Houge_2011), 38.7% of normal activity in a transiently expressed HEK 293H cell system (Lukas_2016), 27% and 46% of normal activity levels respectively in peripheral blood leukocytes from two heterozygous females with random X-chromosome inactivation (Echevarria_2016) and 58.3% of normal activity in a validated human embryonic kidney cell (HEK) based amenability assay (Oommen_2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3, Likely Pathogenic/Pathogenic, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for a later onset/mild/variably penetrant phenotype of Fabry Disease. -

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional analysis of p.(I198T) found that it is associated with significant residual enzyme activity (39-65%) (PMID: 27657681, 26415523); Identified in multiple unrelated individuals with reduced alpha galactosidase activity; however many of these individuals were asymptomatic and limited clinical information was provided on individuals described as symptomatic (PMID: 25149322, 21587323, 25511234, 25974833); This variant is associated with the following publications: (PMID: 25511234, 26415523, 25974833, 21587323, 31036492, 35977816, 32161151, 36156392, 37441486, 27657681, 25149322) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2023	- -

GLA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The GLA c.593T>C variant is predicted to result in the amino acid substitution p.Ile198Thr. This variant has been reported in individuals with reduced blood leukocyte alpha-galactosidase A enzyme activity both with and without clinical features of Fabry disease, suggesting it may have reduced penetrance or represent a pseudodeficiency allele (Echevarria et al. 2015. PubMed ID: 25974833; Houge et al. 2011. PubMed ID: 21587323; Pettazoni et al. 2017. PubMed ID: 28749998; Germain et al. 2015. PubMed ID: 25511234; Table S1, Auray-Blais et al. 2015. PubMed ID: 25149322). In vitro functional studies also showed this variant resulted in moderately reduced enzyme activity 40-64% of wild type (Lukas et al. 2015. PubMed ID: 26415523; Table S1, Benjamin et al. 2017. PubMed ID: 27657681). This variant is listed in ClinVar with conflicting interpretations of uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/167142/). This variant is reported in 0.0025% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2022

The p.I198T variant (also known as c.593T>C), located in coding exon 4 of the GLA gene, results from a T to C substitution at nucleotide position 593. The isoleucine at codon 198 is replaced by threonine, an amino acid with similar properties. This variant was first reported in a sample from a male kidney donor with reduced alpha-galactosidase enzyme activity for whom kidney biopsy was abnormal (Houge G et al. Eur. J. Hum. Genet., 2011 Nov;19:1111). This variant has been detected in additional Fabry disease cohorts in individuals with reduced but residual enzyme activity; however, clinical details were limited and no individuals with classic Fabry disease were apparent (Auray-Blais C et al. Clin. Chim. Acta, 2015 Jan;438:195-204; Echevarria L et al. Clin. Genet., 2016 Jan;89:44-54; Pettazzoni M et al. PLoS ONE, 2017 Jul;12:e0181700). One study indicated this variant to result in reduced enzyme activity in vitro (Lukas J et al. Hum. Mutat., 2016 Jan;37:43-51). Based on data from gnomAD, the C allele has an overall frequency of 0.0011% (2/181907) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0025% (2/81184) of European (Non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Migalastat response

Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: yes

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.78

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.5

H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.0

D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0030

D;.

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.81

Gain of disorder (P = 0.0299);.;

MVP

1.0

MPC

2.0

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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