chrX-101398470-A-G

Variant names:

• chrX-101398470-A-G
• rs398123223
• NM_000169.3:c.899T>C

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.899T>C​(p.Leu300Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L300F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32
• Publications: 17 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 37 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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-101398471-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1324465.
• 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-101398470-A-G is Pathogenic according to our data. Variant chrX-101398470-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 92569.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.899T>C	p.Leu300Pro	missense	Exon 6 of 7	NP_000160.1
	GLA	NM_001406747.1		c.1022T>C	p.Leu341Pro	missense	Exon 7 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.899T>C	p.Leu300Pro	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.899T>C	p.Leu300Pro	missense	Exon 6 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3013A>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1022T>C	p.Leu341Pro	missense	Exon 7 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/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:5

Mar 08, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant affects a conserved nucleotide an results in a replacement of a Leucine (L) with a Proline (P). 5/5 in silico tools predict the variant to be disease causing. The variant is absent from the large and broad cohorts of the ExAC project but was reported in several Fabry patients (Benjamin_JIMD_200; Wu_HM_2011, Lenders_Neurology_2015) indicating pathogenicity. Several independent publications report the variant to result in loss of -Gal A Activity, further supporting a deleterious outcome (Benjamin_JIMD_2009; Shin_Biochem Biophys Res Commun_2007; Wu_HM_2011). Of note, in the presence of DGJ (DGJ, migalastat hydrochloride, AT1001)) -Gal A activity increased 36 times in T cells derived from variant carrier patients (Shin_Biochem Biophys Res Commun_2007) suggesting that patients with the variant of interest migh benefit from DGJ therapy. Additionally, a reputable data base and ClinVar lists variant as pathogenic. Moreover, HGMD lists variants affecting the same codon (c.899T>A, p.Leu300His; c. c.898C>T, p.Leu300Phe) as pathogenic, indicating the variant to be located in a mutational hotspot and suggesting a particular functional importance of the Leu300 residue. Considering all evidence, the variant was classified as Pathogenic.

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 18698230, 19387866). ClinVar contains an entry for this variant (Variation ID: 92569). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Leu300 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 22004918, 28728877), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 300 of the GLA protein (p.Leu300Pro).

Sep 05, 2024

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.899T>C is a missense variant that changes the amino acid at residue 300 from Leucine to Proline. This variant has been observed in at least one proband affected with Fabry disease (PMID:27657681;33072516;30386727;33954932;38002959;35470680). The variant was found to segregate with disease in at least one affected family (PMID:38002959). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:21598360;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.899T>C as a pathogenic variant.

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Oct 01, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0068)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		1.0
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: rs398123223; hg19: chrX-100653458;