dbSNP rs869312135: GLA:p.Leu21Pro (chrX-101407842-A-G) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000169.3(GLA):c.62T>C(p.Leu21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,146 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L21F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 3.13

Publications

4 publications found

Variant links:

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]

GLA links:

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]

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 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-101407842-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087361.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, 0.938

PP5

Variant X-101407842-A-G is Pathogenic according to our data. Variant chrX-101407842-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217374.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLA	NM_000169.3	MANE Select	c.62T>C	p.Leu21Pro	missense	Exon 1 of 7	NP_000160.1
GLA	NM_001406747.1		c.62T>C	p.Leu21Pro	missense	Exon 1 of 8	NP_001393676.1
GLA	NM_001406748.1		c.62T>C	p.Leu21Pro	missense	Exon 1 of 6	NP_001393677.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLA	ENST00000218516.4	TSL:1 MANE Select	c.62T>C	p.Leu21Pro	missense	Exon 1 of 7	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4094A>G		intron	N/A	ENSP00000386655.4
GLA	ENST00000649178.1		c.62T>C	p.Leu21Pro	missense	Exon 1 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112146

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30862

American (AMR)

AF:

0.00

AC:

AN:

10666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1511

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:3

Apr 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 21 of the GLA protein (p.Leu21Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has been observed in individuals affected with GLA-related conditions (PMID: 26415523, 30038331, Invitae). ClinVar contains an entry for this variant (Variation ID: 217374). This variant has been reported to affect GLA protein function (PMID: 26415523). For these reasons, this allele has been classified as Likely Pathogenic.

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Sep 19, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

GLA c.62T>C is a missense variant that changes the amino acid at residue 21 from Leucine to Proline. This variant has been observed in at least one proband affected with Fabry disease (PMID:26415523;32023956;30038331). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;26415523;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 p.Leu21Pro (c.62T>C) as a pathogenic variant.

Migalastat response

Other:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

CardioboostCm

Uncertain

0.19

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

1.9

PhyloP100

3.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.022

Polyphen

0.97

Vest4

0.97

MutPred

0.82

Loss of helix (P = 0.0041)

MVP

1.0

MPC

1.9

ClinPred

0.82

GERP RS

5.4

PromoterAI

-0.0069

Neutral

(source)

Varity_R

0.71

gMVP

0.96

Mutation Taster

=80/20

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over