chrX-101398468-G-C

Variant names:

• chrX-101398468-G-C
• rs398123224
• NM_000169.3:c.901C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000169.3(GLA):​c.901C>G​(p.Arg301Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,091,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 1.43
• Publications: 50 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 13 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, 14 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398467-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1455597.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, 0.989
• PP5: Variant X-101398468-G-C is Pathogenic according to our data. Variant chrX-101398468-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 179546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.901C>G	p.Arg301Gly	missense	Exon 6 of 7	NP_000160.1
	GLA	NM_001406747.1		c.1024C>G	p.Arg342Gly	missense	Exon 7 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.901C>G	p.Arg301Gly	missense	Exon 6 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.901C>G	p.Arg301Gly	missense	Exon 6 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3011G>C		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1024C>G	p.Arg342Gly	missense	Exon 7 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1091099 Hom.: 0 Cov.: 30 AF XY: 0.00000561 AC XY: 2 AN XY: 356769

African (AFR) AF: 0.00 AC: 0 AN: 26271

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.00 AC: 0 AN: 53988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000598 AC: 5 AN: 835667

Other (OTH) AF: 0.00 AC: 0 AN: 45829

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:6

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.901C>G is a missense variant that changes the amino acid at residue 301 from Arginine to Glycine. This variant has been observed in at least one proband affected with Fabry disease (PMID:36292965;30085001;32647377;29626078;30879055;21700093;26298600;32023956;35548424). The variant was found to segregate with disease in at least one affected family (PMID:30085001;35548424;29626078). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:32023956;26298600;31899485;25409744;31996269;35548424;30085001;32647377;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.901C>G as a likely pathogenic variant.

Feb 24, 2021

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.901C>G (p.Arg301Gly) 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 183457 control chromosomes. c.901C>G has been reported in the literature in multiple individuals affected with Fabry Disease, and in some patients specifically with reported Anderson-Fabry disease (Calcagnino_2011, Romani_2015, Liguori_2017, Shabeer_2002, Spinelli_2020). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown the variant to have reduced alpha-Gal activity in vitro: enzyme activity was 19.3% of wild-type, which increased to 56.5% with the addition of Migalastat (Lukas_2013); similarly the variant was reported with in vitro activity of 19.1% of wild-type, which increased to 64.7% of with the addition of Migalastat (Benjamin_2016). 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.

Jan 19, 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 glycine, which is neutral and non-polar, at codon 301 of the GLA protein (p.Arg301Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 12175777, 28672034; internal data). ClinVar contains an entry for this variant (Variation ID: 179546). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 23935525, 27657681). This variant disrupts the p.Arg301 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2171331, 8738659, 9395081, 11688386, 15702404, 20505683, 21598360, 22241068, 23378663). 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.

Mar 06, 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 glycine at codon 301 of the GLA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Multiple in vitro functional studies have shown that this variant causes a greater than 80% reduction in residual GLA enzyme activity (PMID: 23935525, 27657681, 32023956). This variant has been reported in over ten unrelated individuals affected with Fabry disease, including both males and females affected with both classic and atypical Fabry (PMID: 12175777, 21700093, 25655062, 26298600, 27825144, 28936893, 29626078, 30085001, 32647377, 32306159, 35548424, 36292965). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29626078, 30085001, 35548424, 36292965). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg301Gln, is considered to be disease-causing (ClinVar variation ID: 10715), suggesting that arginine at this position is important for GLA protein function. Based on the available evidence, this variant is classified as Pathogenic.

Apr 25, 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 glycine at codon 301 of the GLA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Multiple in vitro functional studies have shown that this variant causes a greater than 80% reduction in residual GLA enzyme activity (PMID: 23935525, 27657681, 32023956). This variant has been reported in over ten unrelated individuals affected with Fabry disease, including both males and females affected with both classic and atypical Fabry (PMID: 12175777, 21700093, 25655062, 26298600, 27825144, 28936893, 29626078, 30085001, 32647377, 32306159, 35548424, 36292965). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29626078, 30085001, 35548424, 36292965). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg301Gln, is considered to be disease-causing (ClinVar variation ID: 10715), suggesting that arginine at this position is important for GLA protein function. Based on the available evidence, this variant is classified as Pathogenic.

not provided Pathogenic:1

Oct 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Pathogenic:1

Apr 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R301G pathogenic mutation (also known as c.901C>G), located in coding exon 6 of the GLA gene, results from a C to G substitution at nucleotide position 901. The arginine at codon 301 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in numerous individuals with Fabry disease, having low enzyme activity observed (Shabbeer J et al. Mol Genet Metab, 2002 May;76:23-30; Calcagnino M et al. J Am Coll Cardiol, 2011 Jun;58:88-9; Romani I et al. J Stroke Cerebrovasc Dis, 2015 Nov;24:2588-95; Esposito R et al. Eur Heart J Cardiovasc Imaging, 2019 Apr;20:438-445; Citro R et al. Front Cardiovasc Med, 2022 Apr;9:838200; Di Risi T et al. Int J Mol Sci, 2022 Oct;23:[ePub ahead of print]). Another alteration at the same codon, p.R301Q (c.902G>A), has been detected in individuals with Fabry disease, who had reduced enzyme activity (Sakuraba H et al. Am J Hum Genet. 1990;47:784-789; Shin SH et al Biochem. Biophys. Res. Commun. 2007 Jul;359(1):168-73; Sawada K et al. Clin. Nephrol. 1996 May;45:289-294). In vitro studies showed this alteration impacts protein function (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Benjamin ER et al. Genet Med, 2017 Apr;19:430-438). 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.

not specified Uncertain:1

Feb 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg301Gly v ariant in GLA has been listed in HGMD as reported in an individual with Fabry di sease, though that publication could not be found. Studies have shown that this variant leads to reduce, but residual GLA function (Lukas 2013); however, this i n vitro assay may not accurately represent biological function. This variant was absent from large population studies. Other missense variants at this position (Arg301Gln, Arg301Pro) have been reported in individuals with Fabry disease (Sak uraba 1990, Ashley 2001), suggesting that variation at this position may not be tolerated, though additional studies are needed. Computational prediction tools and conservation analysis suggest that the Arg301Gly variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . Although this data supports that this variant may be pathogenic, additional st udies are needed to fully assess its clinical significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Loss of solvent accessibility (P = 0.0509)
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.96
gMVP		0.99
Mutation Taster		=7/93	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: rs398123224; hg19: chrX-100653456;