3-33072613-C-T

Position:

chr3-33072613-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000404.4(GLB1):c.176G>A(p.Arg59His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:2

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1

Transcript NM_000404.4 (GLB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000404.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-33072614-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 3-33072613-C-T is Pathogenic according to our data. Variant chr3-33072613-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33072613-C-T is described in Lovd as [Pathogenic]. Variant chr3-33072613-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.176G>A	p.Arg59His	missense_variant	2/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.176G>A	p.Arg59His	missense_variant	2/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249484

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000686

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	GLB1: PM3:Very Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2021	Functional studies in COS-1 cells found that this variant is associated with no residual enzyme activity (Caciotti et al., 2005; Santamaria et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17664528, 10338095, 15714521, 28939701, 10737981, 16466959, 16941474, 31761138, 31216405, 32036093, 33726816) -

Infantile GM1 gangliosidosis

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	High prevalence in Roma and Brazilian populations; associated with GM1 infantile and juvenile forms -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 27, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting, PP4 supporting -

GM1 gangliosidosis type 3

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 18, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 09, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP2. -

Mucopolysaccharidosis, MPS-IV-B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2018	Variant summary: GLB1 c.176G>A (p.Arg59His) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 120758 control chromosomes. c.176G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (Santamaria_2007, Silva_1999), in which two homozygote patients were found to have <10% enzyme activity (Santamaria_2007). These data indicate that the variant is very likely to be associated with disease. A ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 18, 2017	- -

Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 03, 2012	- -

GM1 gangliosidosis type 2

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 18, 2017	- -
not provided, no classification provided	literature only	Laboratory of Molecular Genetics MedGen	-	- -

GLB1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.176G>A;p.(Arg59His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 945; PMID: 10338095; 21637542; 17309651; 16941474; 10737981) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 17664528; 15714521; 31776384) - PS3_moderate. The variant is present at low allele frequencies population databases (rs72555392– gnomAD 0.0003607%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg59His) was detected in trans with a pathogenic variant (PMID: 10338095; 17309651; 16941474; 10737981) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2021

The c.176G>A (p.R59H) alteration is located in exon 2 (coding exon 2) of the GLB1 gene. This alteration results from a G to A substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the GLB1 c.176G>A alteration was observed in 0.0036% (9/249484) of total alleles studied, with a frequency of 0.0087% (3/34526) in the Latino subpopulation. This alteration has been identified in the homozygous state or compound heterozygous with a second GLB1 variant in many patients with infantile (type I) GM1-gangliosidosis (Higaki, 2011; Morrone, 2000; Santamaria, 2006; Santamaria, 2007a; Silva, 1999). This alteration has also been observed with a second GLB1 variant in two patients with the adult form (type III) of GM1 gangliosidosis (Giugliani, 2019). This amino acid position is highly conserved in available vertebrate species. Expression studies have shown this variant is associated with no residual GLB1 enzyme activity (Caciotti, 2005; Santamaria, 2007b). The p.R59H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 59 of the GLB1 protein (p.Arg59His). This variant is present in population databases (rs72555392, gnomAD 0.009%). This missense change has been observed in individuals with GM1 gangliosidosis (PMID: 10338095, 16941474, 17309651, 17664528). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 945). 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) performed at Invitae indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17664528). For these reasons, this variant has been classified as Pathogenic. -

GM1-gangliosidosis, type I, with cardiac involvement

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

GM1 gangliosidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

Across a selection of the available literature, the GLB1 c.176G>A (p.Arg59His) missense variant has been reported in at least three studies and is found in at least 15 individuals with GM1-gangliosidosis, including in ten in a homozygous state and in five in a compound heterozygous state (Silva et al. 1999; Morrone et al. 2000; Santamaria et al. 2007). All of the reported probands presented with infantile GM1-gangliosidosis. The p.Arg59His variant was absent from 200 control chromosomes and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. Functional analysis in proband fibroblasts and COS-7 cells found that the p.Arg59His variant exhibited a nearly complete loss of enzymatic activity compared to wild type (Santamaria et al. 2007). Based on the evidence, the p.Arg59His variant is classified as pathogenic for GM1-gangliosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0070

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.99

MVP

0.98

MPC

0.97

ClinPred

0.94

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.98

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