3-33014292-T-C

Variant names:

• chr3-33014292-T-C
• rs72555368
• NM_000404.4:c.1498A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_000404.4(GLB1):​c.1498A>G​(p.Thr500Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T500S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.84
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• GM1 gangliosidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• GM1 gangliosidosis type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• GM1 gangliosidosis type 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr3-33014292-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2052783.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 0.79419 (below the threshold of 3.09). Trascript score misZ: 1.1264 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 4B, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.
• PP5: Variant 3-33014292-T-C is Pathogenic according to our data. Variant chr3-33014292-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 942.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	c.1498A>G	p.Thr500Ala	missense_variant	Exon 15 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.1498A>G	p.Thr500Ala	missense_variant	Exon 15 of 16	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246730 AF XY: 0.0000224

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461804 Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000341 Hom.: 1

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GM1 gangliosidosis type 3 Pathogenic:1

Oct 17, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PM3 very strong, PP3 supporting -

Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 08, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the GLB1 gene demonstrated a sequence change, c.1498A>G, in exon 15 that results in an amino acid change, p.Thr500Ala. This sequence change has been described in three non-Finnish European individuals in the gnomAD population database (dbSNP rs72555368). This sequence change has been previously described in the compound heterozygous state in individuals with GLB1-related disorders (PMIDs: 10841810, 31497487, 17664528, 26108645). The p.Thr500Ala change affects a highly conserved amino acid residue located in the beta domain 1 of the beta galactosidase 1 (GLB1) protein. Functional studies show p.Thr500Ala disrupts the GLB1 enzymatic activity (PMIDs: 19472408, 12393180). Collectively this evidence suggests p.Thr500Ala is pathogenic. -

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 500 of the GLB1 protein (p.Thr500Ala). This variant is present in population databases (rs72555368, gnomAD 0.003%). This missense change has been observed in individual(s) with Morquio B disease or GM1 gangliosidosis (PMID: 12393180, 17664528, 19472408, 26108645). ClinVar contains an entry for this variant (Variation ID: 942). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. 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:1

Mar 21, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

GM1 gangliosidosis Pathogenic:1

Aug 25, 2022

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.1498A>G (p.Thr500Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246730 control chromosomes. c.1498A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with GM1 Gangliosidosis (example, Bagshaw_2002, Santamaria_2007, Hofer_2009, Kannebley_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 20% of normal beta-galactosidase enzyme activity in-vitro (example, Takai_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.66	D
PhyloP100		5.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.85	.;.;P
Vest4		0.52
MVP		0.96
MPC		0.65
ClinPred		0.96	D
GERP RS		5.8
gMVP		0.82
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72555368; hg19: chr3-33055784;