rs398123355

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000404.4(GLB1):c.481T>G(p.Trp161Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000569 in 1,581,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2O:1

Conservation

PhyloP100: 9.25

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a helix (size 17) in uniprot entity BGAL_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000404.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-33065534-A-C is Pathogenic according to our data. Variant chr3-33065534-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92910.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, not_provided=1, Pathogenic=1}. Variant chr3-33065534-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.481T>G	p.Trp161Gly	missense_variant	5/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.481T>G	p.Trp161Gly	missense_variant	5/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

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:

0.00000499

AC:

AN:

200370

Hom.:

AF XY:

0.00000930

AC XY:

AN XY:

107540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000560

AC:

AN:

1428980

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000549

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

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:

0.0000978

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	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: 25600812, 23337983, 25525159, 21520340, 21497194) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 14, 2018

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 11, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLB1 function (PMID: 23337983). 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. ClinVar contains an entry for this variant (Variation ID: 92910). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 2149194, 25600812). This variant is present in population databases (rs398123355, gnomAD 0.001%). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 161 of the GLB1 protein (p.Trp161Gly). -

GM1 gangliosidosis

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - GM1

Variant identified in multiple family members in the registry. Variant interpreted as Uncertain significance and reported, most recently, on 08-23-2017 by lab or GTR ID Prevention Genetics. 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. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.24

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0050

Sift4G

Benign

0.17

Polyphen

0.97

Vest4

0.37

MutPred

0.69

Loss of sheet (P = 7e-04);

MVP

0.99

ClinPred

1.0

GERP RS

5.6

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