chrX-101398032-C-T

Position:

chrX-101398032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP3_ModerateBS2

The NM_000169.3(GLA):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,095 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. 12/21 in silico tools predict a benign 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. R356P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 3 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 0.296

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 2 ACMG points.

PM1

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

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101398033-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

BS2

High Hemizygotes in GnomAd4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.1067G>A	p.Arg356Gln	missense_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+2575C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.1067G>A	p.Arg356Gln	missense_variant	7/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34185

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183292

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67742

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097090

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

362452

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34185

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.000368

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 02, 2023	This missense variant replaces arginine with glutamine at codon 356 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). This variant has also been reported in over 20 individuals in several Fabry disease screening studies (PMID: 19621417, 20864368, 27238910, 28615118, 29330335, Coutinho et al., 2017, Burlina et al., 2019). Some studies have shown that this variant causes a partial reduction of alpha-galactosidase activity in carriers (PMID: 19621417, 27238910, 28615118, Burlina et al., 2019), while other studies have shown no impact on the enzyme activity (PMID: 23935525, 28615118, 29330335). This variant has been reported in a male individual affected with Fabry disease who also carried another variant of unknown significance in the GLA gene (PMID: 31634893). The proband's sister and daughter both carried these two variants. The sister was affected with left ventricular hypertrophy and microalbuminuria, while the daughter was asymptomatic. This variant has been reported in eight individuals including four males in a family, none of whom had clinical manifestations related to Fabry disease (PMID: 28615118). This variant has been reported in multiple healthy adults in the UK Biobank (PMID: 35977816). This variant has been identified in 2/183292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same codon, p.Arg356Trp, has been associated with Fabry disease and hypertrophic cardiomyopathy (Clinvar variation ID: 10713), suggesting that arginine at this position is important for GLA function. n summary, this variant has been reported in individuals affected with Fabry disease and/or showing reduced GLA enzyme activity and it has also been observed in multiple unaffected individuals. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the GLA protein (p.Arg356Gln). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with GLA-related conditions (PMID: 19621417, 27238910, 28615118, 30477121, 31956509, 31996269). ClinVar contains an entry for this variant (Variation ID: 222135). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 19621417, 23935525, 28615118). This variant disrupts the p.Arg356 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2539398, 17532296, 17555407, 21598360, 24582695, 25611685). 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. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg356Gln variant in GLA has been reported in multiple individuals with Fabry disease (PMID: 19621417, 27238910, 23826564, 28615118), and has been identified in 0.0076% (1/13161) African chromosomes, including one hemizygote, and 0.0012% (1/81755) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869312163). 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 Invitae and as a VUS by EGL Genetic Diagnostics (Variation ID:222135). In vitro functional studies provide some evidence that the p.Arg356Gln variant may slightly impact protein function through decreased GLA enzyme activity (PMID: 28615118, 27238910, 19621417). 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. One additional likely pathogenic variant, causing a different amino acid change at the same position, (p.Arg356Trp), 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: 23935525, 22773828, 17555407, 17532296, 20031620, 23537685, 2539398, 21598360, 22551898, 26415523;Variation ID:217411,10713). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM5_supporting, PS3_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2023	Reported in numerous newborn screening cohorts, in which reduced enzyme activity levels were detected but clinical features varied, including multiple hemizygous adult individuals without clinical manifestations (Hwu et al., 2009, Elliott et al., 2016, Liao et al., 2018; Gilchrist M et al., 2023); Previously reported in males with suspected Fabry disease; detailed clinical and segregation information was not provided (Duro G et al., 2018; Varela P et al., 2020); Published functional studies found this variant retains significant residual enzyme activity (Lukas et al., 2013, Liao et al., 2018; Benjamin ER et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 27238910, 28615118, 19621417, 33597575, 31956509, 30477121, 31634893, 36695159, 27657681, 23935525, 31996269, 35977816, 32531501) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 04, 2023

Variant summary: GLA c.1067G>A (p.Arg356Gln) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Four 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 183292 control chromosomes in gnomAD (including 5 hemizygotes in V4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1067G>A has been reported in the literature in individuals from newborn screening cohorts with reduced enzyme activity (examples: Hwu_2009, Duro_2018, Sawada_2020). However, multiple studies have reported experimental evidence that this variant effect results in >50%-90% of normal activity in vitro (examples: Lukas_2012 and Liao_2018). One study reported that this variant was present in eight individuals from one family but none had clinical abnormalities (Liao_2018). Additionally, a second likely pathogenic variant (GLA p.G360R) was reported in a male patient affected with left ventricular hypertrophy and stroke (Carvalho_ 2019). These report(s) do not provide unequivocal conclusions about association of the variant with Fabry Disease. The following publications have been ascertained in the context of this evaluation (PMID: 19621417, 23935525, 30477121, 28615118, 31634893, 31956509). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2021

The p.R356Q variant (also known as c.1067G>A), located in coding exon 7 of the GLA gene, results from a G to A substitution at nucleotide position 1067. The arginine at codon 356 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in numerous lysosomal storage disease newborn screening cohorts, in which reduced α-Gal A enzyme activity levels were detected (Hwu WL et al. Hum Mutat, 2009 Oct;30:1397-405; Elliott S et al. Mol Genet Metab, 2016 08;118:304-9; Duro G et al. Int J Mol Sci, 2018 Nov;19; Liao HC et al. Mol Genet Metab, 2018 02;123:140-147; Wasserstein MP et al. Genet Med, 2019 03;21:631-640). However, functional studies demonstrate significant residual enzyme activity levels that tentatively support this variant might not cause disease or might cause only mild effects (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Liao HC et al. Mol Genet Metab, 2018 02;123:140-147). This amino acid position is poorly conserved in available vertebrate species, and glutamate is the reference amino acid in several vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.94

D;.

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

0.17

N;.

MutationTaster

Benign

0.66

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.2

N;.

REVEL

Uncertain

0.53

Sift

Benign

0.11

T;.

Sift4G

Benign

0.13

T;.

Polyphen

0.19

B;.

Vest4

0.12

MutPred

0.86

Loss of MoRF binding (P = 0.0857);.;

MVP

0.99

MPC

0.82

ClinPred

0.057

GERP RS

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.81

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