rs869312141

chrX-101403908-A-GchrX-101403908-A-T

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.272T>C(p.Ile91Thr) 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. I91N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-101403908-A-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 217382.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-101403908-A-G is Pathogenic according to our data. Variant chrX-101403908-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 222204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101403908-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.272T>C	p.Ile91Thr	missense_variant	2/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-8028A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.272T>C	p.Ile91Thr	missense_variant	2/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2022	Published functional studies demonstrate a significantly reduced enzyme activity compared to wildtype activity (Ishii et al., 2007; Park et al., 2009; Wu et al., 2011; Lukas et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25655062, 27356758, 27560961, 28723748, 29853467, 25382311, 34679477, 27916943, 33714629, 34922431, 9100224, 17555407, 21598360, 23935525, 26415523, Cai2012, Monte2022, Carnicer-Caceres2022, 32023956, 33915609, 19387866, 33922740, 17894781, 20505683, 23430946, 30477121, 30099469, 19287194) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -

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	Jul 13, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 17555407, 21598360, 26415523). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 222204). This missense change has been observed in individuals with Fabry disease (PMID: 9100224, 19287194, 23935525, 27560961). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 91 of the GLA protein (p.Ile91Thr). -

GLA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2023

The GLA c.272T>C variant is predicted to result in the amino acid substitution p.Ile91Thr. This variant was reported in multiple individuals with Fabry disease (Eng et al. 1997. PubMed ID: 9100224; Ishii et al. 2007. PubMed ID: 17555407; Park et al. 2009. PubMed ID: 19287194; Wu et al. 2011. PubMed ID: 21598360; Lukas et al. 2013. PubMed ID: 23935525; Duro et al. 2018. PubMed ID: 30477121; Pan et al. 2016. PubMed ID: 27560961; Goicoechea et al. 2021. PubMed ID: 33714629). In vitro functional studies show that this variant results in absent or severely reduced alpha-galactosidase A enzymatic activity (Figure 1, Park et al. 2009. PubMed ID: 19287194; Table 1, Wu et al. 2011. PubMed ID: 21598360). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Uncertain	0.90
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.90		Loss of stability (P = 0.0141);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
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: rs869312141; hg19: chrX-100658896;