dbSNP rs564428355: GLB1:p.Arg442Gln (chr3-33018470-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000404.4(GLB1):c.1325G>A(p.Arg442Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,614,032 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000754700: Experimental studies have shown that this missense change affects GLB1 function (PMID:16314480, 18571950)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R442R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.65

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

GM1 gangliosidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
GM1 gangliosidosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
mucopolysaccharidosis type 4B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, 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: Genomics England PanelApp, Orphanet

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000754700: Experimental studies have shown that this missense change affects GLB1 function (PMID: 16314480, 18571950).; SCV001792786: Published functional studies demonstrate that p.(R344Q) seriously impairs enzymatic activity, measured in transiently transfected COS-1 cells (PMID: 16314480); SCV004047843: Experimental studies have shown that this missense change impairs enzymatic activity in vitro (Caciotti et al., 2009; Caciotti et al., 2005).; SCV005352190: This variant has been reported in the compound heterozygous state in individuals with GM1-Gangliosidosis and shown using in vitro studies to negatively affect enzymatic activity (Caciotti et al. 2005. PubMed ID: 16314480; Caciotti et al. 2009. PubMed ID: 18571950; Caciotti et al. 2011. PubMed ID: 21497194; Kumar et al. 2016. PubMed ID: 27679996).; SCV005849195: Experimental studies have shown that this missense change affects GLB1 function (Caciotti et al., 2005; Caciotti et al., 2009).

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000404.4

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 3, GM1 gangliosidosis type 2, GM1 gangliosidosis type 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 3-33018470-C-T is Pathogenic according to our data. Variant chr3-33018470-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 528328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLB1	NM_000404.4	MANE Select	c.1325G>A	p.Arg442Gln	missense	Exon 13 of 16	NP_000395.3
GLB1	NM_001317040.2		c.1469G>A	p.Arg490Gln	missense	Exon 14 of 17	NP_001303969.2
GLB1	NM_001079811.3		c.1235G>A	p.Arg412Gln	missense	Exon 13 of 16	NP_001073279.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLB1	ENST00000307363.10	TSL:1 MANE Select	c.1325G>A	p.Arg442Gln	missense	Exon 13 of 16	ENSP00000306920.4	P16278
GLB1	ENST00000307377.12	TSL:1	c.932G>A	p.Arg311Gln	missense	Exon 10 of 13	ENSP00000305920.8	E7EQ29
GLB1	ENST00000399402.7	TSL:2	c.1235G>A	p.Arg412Gln	missense	Exon 13 of 16	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.0000561

AC:

AN:

249578

AF XY:

0.0000591

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41508

American (AMR)

AF:

0.000458

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000910

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (2)

GLB1-related disorder (1)

GM1 gangliosidosis type 2 (1)

GM1 gangliosidosis type 3 (1)

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

Infantile GM1 gangliosidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

PhyloP100

5.7

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.92

MutPred

0.76

Gain of glycosylation at Y444 (P = 0.0075)

MVP

0.97

MPC

0.93

ClinPred

0.96

GERP RS

5.3

gMVP

0.92

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over