chr3-33016819-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000404.4(GLB1):c.1369C>T(p.Arg457*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000805 in 1,613,910 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GLB1
NM_000404.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.97

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.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-33016819-G-A is Pathogenic according to our data. Variant chr3-33016819-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4 link	c.1369C>T	p.Arg457*	stop_gained	Exon 14 of 16	ENST00000307363.10	NP_000395.3	P16278

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 link	c.1369C>T	p.Arg457*	stop_gained	Exon 14 of 16	1	NM_000404.4	ENSP00000306920.4		P16278

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249532

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000216

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile GM1 gangliosidosis

Pathogenic:4

Sep 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained c.1369C>Tp.Arg457Ter variant in GLB1 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with GM1 gangliosidosis Fu F, et al., 2018; Bidchol AM, et al., 2015; Santamaria R, et al., 2007. The c.1369C>T variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Computational evidence MutationTaster - Disease causing predicts damaging effect on protein structure and function for this variant.The nucleotide change c.1369C>T in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg457Ter in the GLB1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in GLB1 gene have been previously reported to be disease causing Brunetti-Pierri N, Scaglia F., 2008. For these reasons, this variant has been classified as Pathogenic. -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLB1: PM3:Strong, PVS1:Strong, PM2, PP4 -

Sep 05, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

May 19, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GM1 gangliosidosis

Pathogenic:1

Jan 06, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLB1 c.1369C>T (p.Arg457X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 249532 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in individuals affected with GM1 gangliosidosis (e.g. Nishimoto_1991, Santamaria_2007, Matalonga_2015). These data indicate that the variant is likely to be associated with disease. Cells expressing the variant were shown to have indetectable levels of acid beta-galactosidase enzymatic activity (Nishimoto_1991). One Clin Var submitter (evaluation after 2014 ) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg457*) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs72555359, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with GM1 gangliosidosis (PMID: 1909089, 25936995, 28976722, 30548430). ClinVar contains an entry for this variant (Variation ID: 924). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis type 2

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained c.1369C>T (p.Arg457Ter) variant in GLB1 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with GM1 gangliosidosis (Fu et al., 2018; Bidchol et al., 2015; Santamaria et al., 2007). Experimental studies showed that cells expressing the variant had indetectable levels of acid beta-galactosidase enzymatic activity (Nishimoto, 1991). The c.1369C>T variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.1369C>T in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg457Ter) in the GLB1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in GLB1 gene have been previously reported to be disease causing (Brunetti-Pierri and Scaglia, 2008). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

Vest4

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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