rs72555360

chr3-33058221-G-A

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.601C>T(p.Arg201Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,140 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. R201H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.65

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 disulfide_bond (size 35) in uniprot entity BGAL_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) 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 chr3-33058220-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 198077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 3-33058221-G-A is Pathogenic according to our data. Variant chr3-33058221-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33058221-G-A is described in Lovd as [Pathogenic]. Variant chr3-33058221-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.601C>T	p.Arg201Cys	missense_variant	6/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.601C>T	p.Arg201Cys	missense_variant	6/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000442 AC: 11 AN: 249004 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135164

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: 0.0000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GM1 gangliosidosis type 2 Pathogenic:4 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	Variant interpreted as Pathogenic and reported on 08-11-2016 by lab or GTR ID Hudson Alpha. GenomeConnect - GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 14, 2016	- -
Pathogenic, criteria provided, single submitter	research	Dr. Faghihi's Medical Genetic Center	Jan 20, 2017	Four cases affected by GM1 gangliosidosis type II from three consanguineous families showed a homozygote missense mutation in GLB1 gene (c. 601 G> A, p.R201C). Their clinical findings were as follow: Family I, Patient I: A 6.5-year-old girl was referred to the Pediatric Neurology Department in the Mofid Children Hospital, Tehran, Iran due to progressive ataxia and neurodevelopmental regression. She was born from a consanguineous marriage (first-degree cousins) with uneventful birth history. She had normal neurodevelopmental milestones up to the age of three years when she developed progressive ataxia. She gradually lost her lingual and motor skills and became wheelchair-dependent by the age of 5 years. Although she was reported to have normal intellectual abilities, her mental abilities decreased over the course of disease. Detailed neurological exam was performed in the first admission and in the subsequent visits, which revealed neurodevelopmental regression, reduction of age-related intellectual abilities and nystagmus. The “Fix and Follow test” of moving objects was not normal and she gradually lost her vision. Two magnetic resonance imaging (MRI) (in the third and fourth) assessments revealed minor signal changes in the periventricular white matter without any progression (Figure 1a and 1b). Ophthalmologic study did not show any pathologic signs and all metabolic studies were reported in normal range. Electroencephalography (EEG), Visual Evoked Potential (VEP) and Electroretinography (ERG) were normal.. Regarding her family history, 4 members in her mother’s family died due to similar clinical presentations. Family II, Patient II & III: The family had two affected individuals who were referred to the Pediatric Neurology Department in the Mofid Children Hospital, Tehran, Iran due to neurodevelopmental regression. These two siblings, a 9-year-old boy and a 4-year-old girl, had normal developmental milestones up to the age of 3 years. The boy showed progressive ataxia, dystonia and mental decline. All metabolic studies and routine laboratory data were in normal ranges. MRI study showed mild cerebellar atrophy with mild signal changes in the periventricular white matter (Figure 2). The affected girl had similar symptoms with loss of her acquired motor and lingual abilities after the age of 3 years as well as progressive ataxia, speech problem and neurodevelopmental regression. The parents are first-degree cousins who have one unaffected child and positive history of multiple deceased individuals with similar clinical presentation in their extended family. Family III, Patient IV: The patient is an 8-years old girl, who is already bed-ridden and living in the same village as the family II. She was reported to have similar findings to the family II which include progressive ataxia, neurodevelopmental regression, loss of speech and mental decline started around the age of 3 years. Her parents are first-degree cousins and have history of unexplained death of children in their extended families from both sides. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 30, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Identified in multiple unrelated individuals with type II (late infantile/juvenile) GM1-gangliosidosis who were homozygous for R201C or heterozygous for R201C and another variant in GLB1 (Yoshida et al. 1991; Nishimoto et al., 1991; Hofer et al., 2009; Utz et al., 2015; Regier et al., 2016); Functional studies found that R201C is associated with approximately 3-12% residual beta-galactosidase activity (Yoshida et al., 1991; Caciotti et al. 2003; Hofer el al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20409738, 20826101, 24156116, 16626397, 10737981, 16617000, 16538002, 17994547, 18937943, 15744523, 21504867, 8068159, 28716012, 29439846, 8112731, 33737400, 15943552, 22436580, 11511921, 12644936, 22033734, 21144509, 20175788, 25600812, 23151865, 17664528, 18202827, 16763919, 25443580, 24024947, 23337983, 21520340, 19472408, 22784478, 21517827, 25151393, 18546276, 16314480, 23820649, 14676316, 19812739, 1928092, 25925601, 28554332, 30581635, 1907800, 25557439, 26646981, 1909089, 33859490, 35029890, 34816592, 33980489) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Infantile GM1 gangliosidosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 30, 2016	- -

GM1 gangliosidosis type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 30, 2016

- -

Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 30, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GLB1 protein (p.Arg201Cys). This variant is present in population databases (rs72555360, gnomAD 0.009%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 1907800, 25443580, 28554332, 28716012, 29439846). ClinVar contains an entry for this variant (Variation ID: 925). 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: 16617000). This variant disrupts the p.Arg201 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9203065, 11511921, 17309651, 20175788, 23430499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The GLB1 c.601C>T (p.Arg201Cys) missense variant has been reported in four studies in which it is found in a total of eight individuals with GM1 gangliosidosis including in one in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state where a second variant was not identified (Yoshida et al. 1991; Nishimoto et al 1991; Caciotti et al 2003; Takenouchi et al 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Caciotti et al. (2003) investigated the functional impact of GLB1 variants through expression studies in COS-1 cells and demonstrated that the p.Arg201Cys variant resulted in 12.9% of wild type activity. Based on the evidence, the p.Arg201Cys variant is classified as likely pathogenic for GM1 gangliosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.020	D;D;T;D
Vest4		0.97
MVP		0.99
MPC		1.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs72555360; hg19: chr3-33099713; COSMIC: COSV56561720; COSMIC: COSV56561720;