rs192732174

chr3-33068245-G-Achr3-33068245-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000404.4(GLB1):c.442C>T(p.Arg148Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,613,856 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. R148H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.81

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]

ACMG classification

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 chr3-33068244-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 3-33068245-G-A is Pathogenic according to our data. Variant chr3-33068245-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33068245-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.442C>T	p.Arg148Cys	missense_variant	4/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.442C>T	p.Arg148Cys	missense_variant	4/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249276 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000753 AC: 110 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

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: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile GM1 gangliosidosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 09, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R148C in GLB1 (NM_000404.3) has been observed in several individuals affected with GM1 gangliosidosis or mucopolysaccharidosis type IV (Abdul Mueed Bidchol et al 2015).Experimental studies have shown that this missense change abrogates GLB1 enzymatic activity (Anna Caciotti et al 2007). It has been submitted to ClinVar as Pathogenic.The p.R148C variant is observed in 8/1,13,082 (0.0071%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R148C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 148 of GLB1 is conserved in all mammalian species. The nucleotide c.442 in GLB1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	The heterozygous missense variation in exon 4 of GLB1 gene that results in the amino acid substitution to cysteine for arginine at codon of 148 was detected. The variant c.442C>T (p.Arg148Cys) has not been reported in 1000 genome and has a MAF of 0.004% in the gnomAD database. The insilico prediction of the variant is dIsease causing by MutationTaster and SIFT. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 23, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 29, 2017	- -

GM1 gangliosidosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2017	Across a selection of the available literature, the GLB1 c.442C>T (p.Arg148Cys) missense variant has been reported in at least five cases of GM1 gangliosidosis, including four of type 1 and one of type 3 (Roze et al. 2005; Kooper et al. 2006; Caciotti et al. 2007; Hofer et al. 2010; Caciotti et al. 2011). Among the four type 1 cases, the p.Arg148Cys variant was found in a homozygous state in one terminated fetus and in an individual who died at age two. It was also reported in a compound heterozygous state with a frameshift or complex allele in two unrelated 16-month-old individuals who presented with pyschomotor delay before one year of age. The type 3 case developed progressive generalized dystonia after age 16 and was compound heterozygous for p.Arg148Cys and another missense variant. A sixth individual, who carried a missense variant in trans with the p.Arg148Cys variant, presented at age 13 with gradually worsening lower limb weakness and was diagnosed with mucopolysaccharidosis type IVB (Lei et al. 2012). Inheritance from an unaffected parent was demonstrated in multiple cases. Control data are unavailable for this variant, which is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. COS-1 cells that transiently over-expressed the Arg148Cys GLB1 protein showed no residual β-galactosidase activity compared to cells that expressed the wildtype form (Caciotti et al. 2007), and cultured amniocytes, fibroblasts, and leukocytes from umbilical cord blood from a homozygous case showed decreased activity relative to the reference range (Kooper et al. 2006). Two other missense variants at same position have also been reported in association with GM1 gangliosidosis type 1. Based on the collective evidence, the p.Arg148Cys variant is classified as pathogenic for GLB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2024	Variant summary: GLB1 c.442C>T (p.Arg148Cys) 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 4e-05 in 249276 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLB1 causing GM1 Gangliosidosis (4e-05 vs 0.002), allowing no conclusion about variant significance. c.442C>T has been reported in the literature in multiple individuals affected with GM1 Gangliosidosis or mucopolysaccharidosis (examples: Roze_2005, Kooper_2006, Caciotti_2011, Lei_2012, and Kilic_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15986423, 23151865, 17221873, 30712135, 16674934). ClinVar contains an entry for this variant (Variation ID: 92907). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 08, 2013

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 148 of the GLB1 protein (p.Arg148Cys). This variant is present in population databases (rs192732174, gnomAD 0.007%). This missense change has been observed in individuals with GM1 gangliosidosis or mucopolysaccharidosis type IV (PMID: 15986423, 17221873, 23151865, 25936995). ClinVar contains an entry for this variant (Variation ID: 92907). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17221873). This variant disrupts the p.Arg148 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 10839995, 15986423, 17221873, 23151865, 25936995), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Vest4		0.95
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs192732174; hg19: chr3-33109737; COSMIC: COSV56568961; COSMIC: COSV56568961;