chr3-33072644-G-A

Position:

chr3-33072644-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000404.4(GLB1):c.145C>T(p.Arg49Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,014 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 10.0

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 20 ACMG points.

PS1

Transcript NM_000404.4 (GLB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr3-33072643-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 3-33072644-G-A is Pathogenic according to our data. Variant chr3-33072644-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33072644-G-A is described in Lovd as [Pathogenic]. Variant chr3-33072644-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.145C>T	p.Arg49Cys	missense_variant	2/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.145C>T	p.Arg49Cys	missense_variant	2/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249536

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile GM1 gangliosidosis

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1991	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	A Homozygous missense variation in exon 2 of the GLB1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 49 was detected. The observed variant c.145C>T (p.Arg49Cys) has not been reported in the 1000 genomes and has MAF of 0.001% in gnomAD databases. The in silico prediction of the variant is disease causing by PolyPhen-2 (HumDiv), SIFT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -

Mucopolysaccharidosis, MPS-IV-B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 30, 2021

Variant summary: GLB1 c.145C>T (p.Arg49Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Five 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 249536 control chromosomes. c.145C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) and short stature (example, Huang_2018, Bidchol_2015, Georgiou_2004). These data indicate that the variant is 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 <10% of normal Beta-D galactosidase activity in a homozygous individual (example Bidchol_2015). Two 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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2022

This variant is present in population databases (rs72555358, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 15986423, 30267299), which suggests that this may be a clinically significant amino acid residue. 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: 923). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 15365997, 21520340, 25936995, 26646981; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the GLB1 protein (p.Arg49Cys). -

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

Jan 25, 2018

- -

not provided

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Eurofins Ntd Llc (ga)

Jun 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;.;.;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.9

D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.90

MutPred

0.90

Loss of methylation at R49 (P = 0.022);.;Loss of methylation at R49 (P = 0.022);.;.;

MVP

0.98

MPC

1.0

ClinPred

1.0

GERP RS

5.8

gMVP

0.93

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