rs797044613

chrX-101407780-T-CchrX-101407780-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.79

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]

RPL36A-HNRNPH2 (HGNC:):

ACMG classification

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
GLA	NM_000169.3	c.124A>G	p.Met42Val	missense_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4156T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.124A>G	p.Met42Val	missense_variant	1/7	1	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

Submissions by phenotype

Fabry disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This 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 submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 23, 2018

- -

GLA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The 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

Other links and lift over

dbSNP: rs797044613; hg19: chrX-100662768;