rs869312142

chrX-101403843-A-GchrX-101403843-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.337T>C(p.Phe113Leu) 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. 12/21 in silico tools predict a damaging 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. F113I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.09

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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-101403842-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1459744.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-101403843-A-G is Pathogenic according to our data. Variant chrX-101403843-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 222218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101403843-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.337T>C	p.Phe113Leu	missense_variant	2/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-8093A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.337T>C	p.Phe113Leu	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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 113 of the GLA protein (p.Phe113Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease, often with late onset (PMID: 16773563, 17555407, 32099817). It is commonly reported in individuals of Portuguese ancestry (PMID: 32099817). ClinVar contains an entry for this variant (Variation ID: 222218). 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: 16773563, 17555407, 32099817). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2020	Variant summary: GLA c.337T>C (p.Phe113Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183395 control chromosomes. c.337T>C has been reported in the literature in numerous individuals affected with Fabry Disease and is reported as a variant causing late-onset disease (Oliveria_2020, Park_2009, Nowak_2017). The variant showed significantly reduced alpha-Gal activity in both patient fibroblasts and COS-7 cells transfected with the variant, and showed responsive to 1-deoxygalactonojirimycin (DGJ) (Park_2009, Ishii_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo	Dec 16, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 10, 2022

- -

Fabry disease, cardiac variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 09, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2020

The p.F113L pathogenic mutation (also known as c.337T>C), located in coding exon 2 of the GLA gene, results from a T to C substitution at nucleotide position 337. The phenylalanine at codon 113 is replaced by leucine, an amino acid with highly similar properties. This mutation was detected in an adult male with residual alpha-galactosidase A enzyme activity and reported cardiac-variant Fabry disease whose carrier mother also had cardiac manifestations (Eng CM et al. Mol. Med., 1997 Mar;3:174-82). Subsequently, this mutation has been reported as a Portuguese founder mutation, having been detected in multiple individuals and families with Fabry disease, frequently presenting with late-onset cardiac-variant phenotoype; however, additional features of Fabry disease in individuals with this mutation have also been reported (Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Park JY et al. Exp. Mol. Med., 2009 Jan;41:1-7; Nowak A et al. Mol. Genet. Metab., 2018 02;123:148-153; Azevedo O et al. Mol. Genet. Metab., 2019 Jul; Oliveira JP et al. Eur J Med Genet, 2019 Jun;103703). In addition, several functional assays have shown this mutation to result in reduced enzyme activity in vitro (Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Park JY et al. Exp. Mol. Med., 2009 Jan;41:1-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.99		Gain of disorder (P = 0.1034);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
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: rs869312142; hg19: chrX-100658831;