rs72555393

Positions:

chr3-33072544-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000404.4(GLB1):c.245C>T(p.Thr82Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense, splice_region

Scores

Splicing: ADA: 0.00008291

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.07

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 12 ACMG points.

PM1

In a strand (size 5) in uniprot entity BGAL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000404.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-33072544-G-A is Pathogenic according to our data. Variant chr3-33072544-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33072544-G-A is described in Lovd as [Pathogenic]. Variant chr3-33072544-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLB1	NM_000404.4 link	c.245C>T	p.Thr82Met	missense_variant, splice_region_variant	2/16	ENST00000307363.10	NP_000395.3	P16278

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 link	c.245C>T	p.Thr82Met	missense_variant, splice_region_variant	2/16	1	NM_000404.4	ENSP00000306920.4		P16278

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

249296

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460814

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000537

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GM1 gangliosidosis type 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.245C>T p.Thr82Met variant in the GLB1 gene has been observed in individuals with GM1-gangliosidosis Hofer, D et al., 2010. It has also been observed to segregate with disease in related individuals. Functional studies demonstrate decreased enzyme activity Chakraborty et al., 1994. This variant is reported with the allele frequency 0.005% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/Uncertain significance/Pathogenic multiple submissions. The amino acid Threonine at position 82 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr82Met in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

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	Feb 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 30, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2021

Published functional studies demonstrate decreased enzyme activity (Chakraborty et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 19472408, 11511921, 31367523, 8198123, 24024947, 25326637, 20175788, 31761138, 31937438, 31628766, 21520340, 6791574, 33240792) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the GLB1 protein (p.Thr82Met). This variant is present in population databases (rs72555393, gnomAD 0.009%). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 8198123, 11511921, 20175788, 21520340, 25326637). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 8198123). For these reasons, this variant has been classified as Pathogenic. -

Infantile GM1 gangliosidosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The stop gain c.1324C>T p.Arg442Ter variant in GLB1 gene has been reported to the ClinVar database as Pathogenic. To our knowledge, this variant has not been reported in literature in individuals affected with GLB1-associated disorder. The c.1324C>T variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. The nucleotide change c.1324C>T in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.63

MetaSVM

Pathogenic

1.0

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

Sift4G

Benign

0.15

Polyphen

0.13

Vest4

0.21

MVP

0.97

ClinPred

0.60

GERP RS

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.088

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