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rs797044613

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000169.3(GLA):c.124A>G(p.Met42Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M42L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

GLA
NM_000169.3 missense

Scores

12
4
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.79
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000169.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-101407780-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant X-101407780-T-C is Pathogenic according to our data. Variant chrX-101407780-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 222174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407780-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLANM_000169.3 linkuse as main transcriptc.124A>G p.Met42Val missense_variant 1/7 ENST00000218516.4
RPL36A-HNRNPH2NM_001199973.2 linkuse as main transcriptc.301-4156T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLAENST00000218516.4 linkuse as main transcriptc.124A>G p.Met42Val missense_variant 1/71 NM_000169.3 P1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fabry disease Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 30, 2023This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 42 of the GLA protein (p.Met42Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 8875188, 18205205, 19287194). ClinVar contains an entry for this variant (Variation ID: 222174). 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: 19287194, 23935525). This variant disrupts the p.Met43 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15492942, 15712228, 27657681). 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 23, 2018- -
GLA-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 12, 2024The GLA c.124A>G variant is predicted to result in the amino acid substitution p.Met42Val. This variant was reported in individuals with Fabry disease (Davies et al. 1996. PubMed ID: 8875188; Shimotori et al. 2008. PubMed ID: 18205205; Park et al. 2009. PubMed ID: 19287194) and in high-risk screening for Fabry disease (Yoshida et al. 2020. PubMed ID: 32843101). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant impacts protein function (Lukas et al. 2013. PubMed ID: 23935525; Park et al. 2009. PubMed ID: 19287194; Shimotori et al. 2008. PubMed ID: 18205205). Alternate nucleotide changes affecting the same amino acid (p.Met42Leu; p.Met42Thr; p.Met42Arg; p.Met42Ile), have been reported in individuals with Fabry disease (Rosenthal et al. 2004. PubMed ID: 15492942; Shabbeer et al. 2002. PubMed ID: 12175777; Riera et al. 2015. PubMed ID: 25382311; Pan et al. 2016. PubMed ID: 27560961). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
CardioboostCm
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.71
D
BayesDel_noAF
Pathogenic
0.78
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D;.
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.0
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.5
D;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.0030
D;.
Polyphen
1.0
D;.
Vest4
0.94
MutPred
0.95
Loss of methylation at R38 (P = 0.1822);Loss of methylation at R38 (P = 0.1822);
MVP
1.0
MPC
1.7
ClinPred
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
1.0

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.

Other links and lift over

dbSNP: rs797044613; hg19: chrX-100662768; API