rs72555393

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

4
6
6
Splicing: ADA: 0.00008291
2

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]

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
GLB1NM_000404.4 linkc.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
GLB1ENST00000307363.10 linkc.245C>T p.Thr82Met missense_variant, splice_region_variant 2/161 NM_000404.4 ENSP00000306920.4 P16278

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152150
Hom.:
0
Cov.:
32
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:
13
AN:
249296
Hom.:
0
AF XY:
0.0000665
AC XY:
9
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:
22
AN:
1460814
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
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:
2
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.0000744
AC:
9

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 providedliterature onlyOMIMJun 01, 1994- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 20, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylAug 30, 2017- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 26, 2016- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 25, 2021Published 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024This 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 submitterclinical testingNeuberg 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
D
BayesDel_noAF
Pathogenic
0.21
CADD
Benign
20
DANN
Uncertain
0.99
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.40
T
M_CAP
Pathogenic
0.51
D
MetaRNN
Uncertain
0.63
D
MetaSVM
Pathogenic
1.0
D
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D
Sift4G
Benign
0.15
T
Polyphen
0.13
B
Vest4
0.21
MVP
0.97
ClinPred
0.60
D
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.

Other links and lift over

dbSNP: rs72555393; hg19: chr3-33114036; API