X-101403846-G-A

Variant names:

• chrX-101403846-G-A
• rs104894834
• NM_000169.3:c.334C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.334C>T​(p.Arg112Cys) variant causes a missense change. 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. R112S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.28
• Publications: 86 publications found

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

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 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-101403846-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4081422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-101403846-G-A is Pathogenic according to our data. Variant chrX-101403846-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.334C>T	p.Arg112Cys	missense_variant	Exon 2 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.334C>T	p.Arg112Cys	missense_variant	Exon 2 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-8090G>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:5

Dec 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 112 of the GLA protein (p.Arg112Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 1315715, 14635108, 18205205, 19287194, 21598360, 23935525). ClinVar contains an entry for this variant (Variation ID: 92550). 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: 1315715, 11137837, 14635108, 19287194, 21598360, 23935525, 26456105). This variant disrupts the p.Arg112 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1315715, 7575533, 11137837, 20505683, 22874111). 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. -

May 25, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.334C>T (p.Arg112Cys) 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 87742 control chromosomes (in ExAC). c.334C>T has been reported in the literature in multiple individuals affected with Fabry Disease, with (hemizygous) males being more severely affected than heterozygous women (e.g. Wilcox 2012, Shin 2008, Pieroni 2003). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (Shin 2008, Pieroni 2003). The most pronounced variant effect results in <10% of normal activity in male patients (hemizygotes). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 09, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 14635108, 19287194, 23935525). This variant has been reported in multiple individuals with Fabry disease (PMID: 1315715, 14635108, 18205205, 19287194, 21598360, 23935525, 36873653, 36383556, 36140787, 35743707). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). A different missense substitution at this amino acid residue has been previously reported in individuals with disease and classified as pathogenic, which supports the functional importance of this position. This variant is predicted to be deleterious by in silico analysis. -

not provided Pathogenic:5

Oct 28, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Published functional studies functional studies have demonstrated that R112C results in reduced enzyme activity compared to the wild-type (Ishii et al., 1992; Yasuda et al., 2003; Lukas et al., 2013); 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: 30477121, 27657681, 28988177, 1315715, 23818648, 26018987, 27160240, 15776423, 23724928, 22551898, 17370152, 25974833, 18849176, 21333496, 7575533, 11668641, 20505683, 7911050, 12428061, 18023222, 10666480, 15712228, 28178158, 26047621, 25382311, 24386359, 23935525, 14635108, 21598360, 18205205, 19287194, 17532296) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 09, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jul 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R112C pathogenic mutation (also known as c.334C>T), located in coding exon 2 of the GLA gene, results from a C to T substitution at nucleotide position 334. The arginine at codon 112 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous Fabry disease cohorts in individuals shown to be clinically affected (Germain DP et al. Mol Med, 2002 Jun;8:306-12; Lee BH et al. J Hum Genet, 2010 Aug;55:512-7; Wang C et al. Kidney Blood Press Res, 2013 Jun;37:221-8; Frustaci A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:799-805; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Barman HA et al. Balkan Med J, 2019 10;36:354-358; Militaru S et al. Curr Health Sci J, 2019 Sep;45:272-277). Functional studies indicated that cells expressing this alteration demonstrated absent alpha-galactosidase enzyme activity and accumulation of elevated levels of Lyso-Gb3 (Yasuda M et al. Hum Mutat, 2003 Dec;22:486-92; Park JY et al. Exp Mol Med, 2009 Jan;41:1-7; Wu X et al. Hum Mutat, 2011 Aug;32:965-77; Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. 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	Uncertain	0.41
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;.
PhyloP100		4.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.91		Loss of disorder (P = 0.0084);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894834; hg19: chrX-100658834; COSMIC: COSV105103411; COSMIC: COSV105103411;