X-101398906-C-T

Variant names:

• chrX-101398906-C-T
• rs104894840
• NM_000169.3:c.680G>A

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.680G>A​(p.Arg227Gln) 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. R227P) 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:13
• Conservation: PhyloP100: 7.84
• Publications: 59 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 34 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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-101398906-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 217394.Status of the report is criteria_provided_single_submitter, 1 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, 0.992
• PP5: Variant X-101398906-C-T is Pathogenic according to our data. Variant chrX-101398906-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.680G>A	p.Arg227Gln	missense	Exon 5 of 7	NP_000160.1
	GLA	NM_001406747.1		c.803G>A	p.Arg268Gln	missense	Exon 6 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.680G>A	p.Arg227Gln	missense	Exon 5 of 6	NP_001393677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.680G>A	p.Arg227Gln	missense	Exon 5 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3449C>T		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.803G>A	p.Arg268Gln	missense	Exon 6 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:9

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 20, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 227 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. In vitro functional studies using transfected HEK-293 cells as well as patient-derived cell lines have shown that this variant causes a significant reduction in GLA enzyme activity (PMID: 18698230, 21598360, 23935525, 32023956). This variant has been reported in at least nine males and eight females affected with Fabry disease (PMID: 10916280, 12920095, 15713906, 28283366, 29132836, 29950951, 30738278, 32813676, 33204599, 33807900, 34877240, 36140787). It has been shown that this variant segregates with disease in multiple affected individuals, both male and female, in one large family (PMID: 20615758). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 14, 2025

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 glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.

Nov 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 227 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. In vitro functional studies using transfected HEK-293 cells as well as patient-derived cell lines have shown that this variant causes a significant reduction in GLA enzyme activity (PMID: 18698230, 21598360, 23935525, 32023956). This variant has been reported in at least nine males and eight females affected with Fabry disease (PMID: 10916280, 12920095, 15713906, 28283366, 29132836, 29950951, 30738278, 32813676, 33204599, 33807900, 34877240, 36140787, 38002959). It has been shown that this variant segregates with disease in multiple affected individuals, both male and female, in one large family (PMID: 20615758). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 09, 2020

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.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.680G>A is a missense variant that changes the amino acid at residue 227 from Arginine to Glutamine. This variant has been observed in at least one proband affected with Fabry disease (PMID:7504405;30371172;33906135;27083555;29950951;25750198;20022777;26303609). The variant was found to segregate with disease in at least one affected family (PMID:990607;999546;1014609;1254749). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;21598360;23935525;27657681). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify GLA c.680G>A as a pathogenic variant.

not provided Pathogenic:4

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); 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: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525)

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 10, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2, PS3, PS4_moderate

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		7.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.97		Loss of MoRF binding (P = 0.0795)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs104894840; hg19: chrX-100653894;