X-101398501-T-G

Position:

chrX-101398501-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The ENST00000218516.4(GLA):c.868A>C(p.Met290Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,206,427 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. M290I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

GLA
ENST00000218516.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:2

Conservation

PhyloP100: 8.02

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 15 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000218516.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101398499-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

PP5

Variant X-101398501-T-G is Pathogenic according to our data. Variant chrX-101398501-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.868A>C	p.Met290Leu	missense_variant	6/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+3044T>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.868A>C	p.Met290Leu	missense_variant	6/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111993

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34141

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67890

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:

9.14e-7

AC:

AN:

1094434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359890

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111993

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34141

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2022	Variant summary: GLA c.868A>C (p.Met290Leu) results in a conservative amino acid change in the encoded protein sequence. Three 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 183454 control chromosomes (gnomAD). c.868A>C has been reported in the literature in individuals affected with Fabry Disease (e.g. Ferri_2012, Zampetti_2013). These data indicate that the variant is likely to be associated with disease. When expressed in a heterologous HEK293 cell assay, the variant had 11.2% normal activitiy (Ferri_2012). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the GLA protein (p.Met290Leu). This variant is present in population databases (rs375538532, gnomAD 0.002%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21517827). ClinVar contains an entry for this variant (Variation ID: 222434). 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 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: 21517827, 23935525). This variant disrupts the p.Met290 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23935525, 27773586, 28728877, 29307789). 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	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Met290Leu variant in GLA has been reported in eight individuals with Fabry disease, has segregated with disease in 7 affected relatives from 2 families (PMID: 23210910, 28069318), and has been identified in 0.0024% (2/81914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375538532). 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 a VUS by Invitae (Variation ID:222434). Computational prediction tools and conservation analyses suggest that this variant may 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 on the classic phenotype that is consistent with disease (PMID: 21517827). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Met290Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 28302345, 23935525, 22773828, 27560961, 16595074). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS4_supporting, PP1_moderate, 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	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2023	This missense variant replaces methionine with leucine at codon 290 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that baseline alpha-galactosidase A activity of the mutant protein was ~60-70% of wild type upon heterologous expression in HEK-293 cells (PMID: 21517827, 32198894). This variant has been reported in individuals affected with Fabry disease (PMID: 21517827, 23210910, 23332617, 28069318, 30477121). Different variants affecting the same codon, c.870G>A p.Met290Ile and c.870G>C p.Met290Ile, are considered to be disease-causing (Clinvar variation ID: 222435 and 222436), suggesting that methionine at this position is important for GLA protein function. This variant has been identified in 2/183454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1Uncertain:2

Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Jan 06, 2020	- -
Uncertain significance, flagged submission	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 26, 2017	Seen in 1 patient in our center with dilated cardiomyopathy. Testing was performed at Invitae. Given the weak case data and different phenotype than would be expected for a disease-causing variant in these gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The GLA gene encodes alphagalacotosidase. Mutations in the GLA cause Fabry disease, an X-linked condition characterized by multi-organ dysfunction. Clinical characteristics include left ventricular hypertrophy, kidney failure, peripheral neuropathy, ophthalmologic and sweating abnormalities. The variant has been seen in at least 1 unrelated case of Fabry disease. It has not been reported in any cases of dilated cardiomyopathy. There is weak case data and some functional data. Ferri et al 2011 reported the variant in a patient with clinical findings suggestive of Fabry disease. She was a 34yo, who had "cardiovascular manifestations, psychiatric symptoms, and cardiomyopathy (type not specified). Her alpha-gal A enzyme level was 11nmol/mg/h. The paper noted that the HEK cells harboring the Met290Leu variant had decreased enzyme levels that were recovered with treatment with the pharmacologic chaperone deoxygalactonojirimycin (DGJ). Lukas et al (2013) found that variant resulted in a 18% wild type alpha-gal A level on in vitro assay. The Met at codon 290 is conserved across species. PolyPhen predicts it to be probably damaging. The variant is present in 2 of 89,369 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,00 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 40,064 individuals of European descent (MAF = 0.002%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22004918, 21517827, 25382311, 28069318, 27657681, 37599028, 37441486, 23935525, 23210910) -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.868A>C (p.M290L) alteration is located in coding exon 6 of the GLA gene. This alteration results from an A to C substitution at nucleotide position 868, causing the methionine (M) at amino acid position 290 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (2/183454) total alleles studied. The highest observed frequency was 0.002% (2/81914) of European (non-Finnish) alleles. This alteration has been detected in individuals reported to have Fabry disease (FD) or features consistent with FD, demonstrating reduced alpha-galactosidase enzyme activity (Ferri, 2012; Zampetti, 2013; Graziani, 2017; Burlina, 2019; Gragnaniello, 2021). This amino acid position is highly conserved in available vertebrate species. In in vitro functional studies, this variant was shown to result in reduced enzyme activity (Ferri, 2012; Lukas, 2013). This alteration is predicted to be deleterious by in silico analysis. 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

0.18

CardioboostCm

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.63

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.63

D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;T

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.39

N;.

REVEL

Pathogenic

0.79

Sift

Benign

0.82

T;.

Sift4G

Benign

0.82

T;.

Polyphen

0.98

D;.

Vest4

0.94

MutPred

0.75

Loss of catalytic residue at M290 (P = 0.0189);.;

MVP

1.0

MPC

1.7

ClinPred

0.49

GERP RS

5.9

Varity_R

0.63

gMVP

0.98

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