rs149391489

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_000169.3(GLA):c.376A>G(p.Ser126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,207,539 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 221 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00057 ( 0 hom. 211 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 2.56

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36750877).

BP6

Variant X-101401803-T-C is Benign according to our data. Variant chrX-101401803-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163547.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=2, Uncertain_significance=2}. Variant chrX-101401803-T-C is described in Lovd as [Pathogenic]. Variant chrX-101401803-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000401 (45/112278) while in subpopulation NFE AF= 0.000769 (41/53300). AF 95% confidence interval is 0.000582. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 10 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.376A>G	p.Ser126Gly	missense_variant	Exon 3 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.376A>G	p.Ser126Gly	missense_variant	Exon 3 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+6346T>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

112278

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34416

show subpopulations

Gnomad AFR

AF:

0.0000648

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.000769

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000327

AC:

AN:

183376

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

67822

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000684

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000565

AC:

619

AN:

1095261

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

211

AN XY:

360735

show subpopulations

Gnomad4 AFR exome

AF:

0.0000759

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000740

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.000697

Gnomad4 OTH exome

AF:

0.000370

GnomAD4 genome

AF:

0.000401

AC:

AN:

112278

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34416

show subpopulations

Gnomad4 AFR

AF:

0.0000648

Gnomad4 AMR

AF:

0.000189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000769

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:2Benign:7

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of Fabry disease (MIM#301500) (gnomAD v2.1.1 - 25 hemizygotes) (SB) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has previously been reported as benign, likely benign and as a variant of uncertain significance (ClinVar). While this variant has also been reported in patients, population frequency supports this variant being benign (PMIDs:29132836; 31860127; 23935525; 33036343; 20360539). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Ser126Gly variant in GLA has been reported in 3 individuals with Fabry disease, segregated with disease in these 3 affected relatives from one family (PMID: 22905681), and has also been identified in 0.074% (69/92714) of European (non-Finnish) chromosomes, including 24 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149391489). This variant has also been reported in ClinVar as likely benign by the Laboratory for Molecular Medicine (Partners Healthcare), GeneDx, and Ambry Genetics and as a VUS by Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) and Invitae (Variation ID: 163547). In vitro functional studies provide some evidence that the p.Ser126Gly variant may not impact protein function (PMID: 23935525, 11889412, 28646478). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ser126Gly variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_supporting, BS3_supporting, PP1 (Richards 2015). -

not provided

Uncertain:1Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLA: BS2 -

Sep 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11889412, 29132836, 23935525, 24582695, 23219219, 26520229, 26652600, 20360539, 23306324, 23307880, 22905681, 25596309, 25382311, 28646478, 28283366, 28340804, 26990548, 29487688, 27657681, 31860127, 30477121) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified

Benign:3

May 29, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser126Gly variant in GLA has been reported in a 12-year-old male with Fabr y disease, 1 adult female with stroke who had normal alpha-galactosidase levels, 1 female with unspecified clinical information, 1 female toddler with LVNC and arthrogryposis, 1 male toddler with neonatal onset DCM, and 2 adult females with HCM (Branton 2012, De Brabander 2013, Pasqualim 2014, LMM data). It has also be en identified in 0.07% (66/90653) of European chromosomes, including 23 hemizygo tes, in the gnomAD database (http://gnomad.broadinstitute.org; dbSNP rs149391489 ). Functional studies indicate that the p.Ser126Gly variant may reduce GLA enzym e function by 50%, but the clinical threshold and impact are not well characteri zed (Lukas 2013). A predictive model developed to determine the pathogenicity of variants in the GLA gene suggests that the p.Ser126Gly variant may not be damag ing (Riera 2015), though this information is not predictive enough to rule out p athogenicity. In summary, while the clinical significance of the p.Ser126Gly var iant is not conclusive, given the population frequency, presence of hemizygotes, inconsistency in phenotype in cases, and residual enzyme activity in functional studies, this variant is likely benign. -

Nov 19, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.376A>G (p.Ser126Gly) results in a non-conservative amino acid change located in the Aldolase class I domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 1207539 control chromosomes, including 221 hemizygotes. c.376A>G has been identified in the literature without strong evidence for pathogenicity (e.g. Branton_2002, Colon_2017, Reisin_2018). At least one family study showed lack of co-segregation of the variant with the disease (DeBrabander_2013, Reisin_2018). In addition, a functional study found that GLA enzyme activity was reduced by ~50% in vitro, but also found that the lyso-Gb3 biomarker that is typically increased in Fabry patients was at normal levels in patient samples with the variant (Lukas_2013). Another in vitro enzyme activity study showed that the variant retained 83% of WT activity levels (Benjamin_2016). A recent study however, showed no significant reduction in enzymatic activity (Oommen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27657681, 11889412, 20360539, 28646478, 23219219, 23935525, 31036492, 24582695, 29132836, 25382311, 30739116, 28340804, 26866599). ClinVar contains an entry for this variant (Variation ID: 163547). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy

Benign:1

Feb 17, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 08, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

CardioboostCm

Benign

0.082

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.37

T;T

MetaSVM

Pathogenic

1.3

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

D;.

REVEL

Pathogenic

0.66

Sift

Benign

0.060

T;.

Sift4G

Benign

0.069

T;.

Polyphen

0.043

B;.

Vest4

0.68

MVP

1.0

MPC

0.70

ClinPred

0.050

GERP RS

3.5

Varity_R

0.75

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over