rs104894827

Positions:

• chrX-101398033-G-A
• chrX-101398033-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.1066C>T​(p.Arg356Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.48

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:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant X-101398033-G-A is Pathogenic according to our data. 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. Variant chrX-101398033-G-A is described in Lovd as [Pathogenic]. Variant chrX-101398033-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.1066C>T	p.Arg356Trp	missense_variant	7/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1066C>T	p.Arg356Trp	missense_variant	7/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2576G>A		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097151 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362519

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2018	The Arg356Trp variant in GLA has been reported in at least 10 individuals with F abry disease or hypertrophic cardiomyopathy, including at least 2 females, and s egregated with disease in 4 clinically or biochemically affected family members across 3 families most of whom had a "mild classic" Fabry disease phenotype (Ber nstein 1989, Lin 2009, Turaca 2012, Romao 2013, Pasqualim 2014, LMM data). This variant was absent from large population studies. Several in vitro functional st udies have shown that this variant is associated with significantly reduced alph a-galactosidase A activity (Wu 2011, Siekierska 2012, Lukas 2013). In summary, t his variant meets criteria to be classified as pathogenic for X-linked Fabry dis ease based on case observations, segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PS4, PM2, PS3_Moderate, PP1, PP 4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 356 of the GLA protein (p.Arg356Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 2539398, 23537685). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10713). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 17555407, 23935525). 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: 19621417, 27238910, 28615118). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1989	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	Published functional studies demonstrate a severe reduction in enzyme activity (Ishii et al., 2007; Wu et al., 2011; Siekierska et al. 2012; Lukas et al., 2013; Germain et al., 2019); 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: 23537685, 25382311, 27532257, 30477121, 17555407, 17532296, 23935525, 24582695, 25611685, 24334114, 32843101, 30879055, 22551898, 21598360, 22773828, 31996269, Neves2020[Article], 19521690, 18633574, 32023956, 24613481, 27916943, 29305833, 33163363, 19156839, 29935990, 20031620, 28615118, 17894781, 32647377, 27825144, 22063097, 18698230, 19387866, Rubino2022[CaseReport], 2539398, 30723321) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2019	- -

GLA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2023

The GLA c.1066C>T variant is predicted to result in the amino acid substitution p.Arg356Trp. This variant has been reported in individuals with Fabry disease (Bernstein et al. 1989. PubMed ID: 2539398; Romão et al. 2013. PubMed ID: 23537685). Functional studies indicate this variant impacts protein solubility, aggregation, and activity (Siekierska et al. 2012. PubMed ID: 22773828; Table S1, Lukas. 2013. PubMed ID: 23935525; Wu et al. 2011. PubMed ID: 21598360). Different missense variants impacting the same amino acid residue (p.Arg356Gln, p.Arg356Pro) have also been reported in individuals with Fabry disease phenotypes or have been shown to impact GLA activity (Hwu et al. 2009. PubMed ID: 19621417; Lukas et al. 2016. PubMed ID: 26415523). 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	Benign	0.10
CardioboostCm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.97	L;.
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.88		Loss of disorder (P = 0.0267);.;
MVP		0.93
MPC		1.6
ClinPred		0.88	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.92

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: rs104894827; hg19: chrX-100653021;