rs72555366

Positions:

chr3-33058200-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_ModeratePM1PM2PP3_ModeratePP5_Very_Strong

The NM_000404.4(GLB1):c.622C>T(p.Arg208Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,086 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 5.24

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 16 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 disulfide_bond (size 35) in uniprot entity BGAL_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_000404.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 3-33058200-G-A is Pathogenic according to our data. Variant chr3-33058200-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33058200-G-A is described in Lovd as [Pathogenic]. Variant chr3-33058200-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLB1	NM_000404.4 link	c.622C>T	p.Arg208Cys	missense_variant	6/16	ENST00000307363.10	NP_000395.3	P16278

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 link	c.622C>T	p.Arg208Cys	missense_variant	6/16	1	NM_000404.4	ENSP00000306920.4		P16278

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

249146

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000316

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2022	Published functional studies demonstrate that the R208C variant abolishes the catalytic activity of the -galactosidase enzyme (Boustany et al., 1993); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28703315, 22128166, 29451896, 8213816, 8652017, 20175788, 15714521, 10571006, 23046582, 17309651, 23337983, 31761138, 32219895, 31905715, 10338095) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2013	- -

Infantile GM1 gangliosidosis

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 03, 2017	- -

GM1 gangliosidosis

Pathogenic:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	Variant classified as Pathogenic and reported on 06-01-2020 by Lab or GTR ID 26957. GenomeConnect-GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2017	Variant summary: The GLB1 c.622C>T (p.Arg208Cys) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. This variant was found in 7/120010 control chromosomes at a frequency of 0.0000583, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLB1 variant (0.0020412). Multiple publications have cited the variant in affected individuals as homozygotes and compound heterozygotes, and observed little to no enzymatic activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

GM1 gangliosidosis type 3

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Feb 03, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

The c.622C>T (p.R208C) alteration is located in exon 6 (coding exon 6) of the GLB1 gene. This alteration results from a C to T substitution at nucleotide position 622, causing the arginine (R) at amino acid position 208 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (11/249146) total alleles studied. This variant has been reported in the homozygous state and confirmed or presumed in trans with a second GLB1 variant in patients with GM1-gangliosidosis (Boustany, 1993; Silva, 1999; Caciotti, 2005; Santamaria, 2007; Arash-Kaps, 2019). This amino acid position is not well conserved in available vertebrate species. In vitro studies demonstrated that this variant abolished catalytic activity of the beta-galactosidase protein in transfected COS-1 cells (Boustany, 1993). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Mucopolysaccharidosis, MPS-IV-B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Feb 03, 2017

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 208 of the GLB1 protein (p.Arg208Cys). This variant is present in population databases (rs72555366, gnomAD 0.02%). This missense change has been observed in individuals with GM1-gangliosidosis (PMID: 8213816, 10338095, 15714521, 17309651). ClinVar contains an entry for this variant (Variation ID: 939). 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: 8213816, 15714521, 23337983). For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis type 2

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Feb 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;.;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;.;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-6.4

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Vest4

0.57

MVP

0.98

MPC

0.94

ClinPred

0.96

GERP RS

4.7

gMVP

0.83

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