rs72555360

Variant names:

• chr3-33058221-G-A
• rs72555360
• NM_000404.4:c.601C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R201H) has been classified as Likely 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:16 O:1
• Conservation: PhyloP100: 7.65
• Publications: 25 publications found

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: Myriad Women’s Health, ClinGen
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), 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: Orphanet, Genomics England PanelApp

ACMG classification

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

• 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/Likely_pathogenic. ClinVar VariationId is 198077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4	c.601C>T	p.Arg201Cys	missense_variant	Exon 6 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.601C>T	p.Arg201Cys	missense_variant	Exon 6 of 16	1	NM_000404.4	ENSP00000306920.4

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

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 249004 AF XY: 0.0000592

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000917 AC: 102 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

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

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000886 Hom.: 1

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:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GM1 gangliosidosis type 2 Pathogenic:5 Other:1

Oct 30, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 14, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GenomeConnect - GM1

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jun 30, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000925 /PMID: 1907800). A different missense change at the same codon (p.Arg201His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000198077). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 20, 2017

Dr. Faghihi's Medical Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

not provided Pathogenic:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies found that R201C is associated with approximately 3-12% residual beta-galactosidase activity (PMID: 12644936, 1907800, 19472408); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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, 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, 25557439, 26646981, 1909089, 33859490, 35029890, 34816592, 33980489, 12644936, 1907800, 38019733, 37381921, 9203065) -

Infantile GM1 gangliosidosis Pathogenic:2

Oct 30, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLB1-related disorder Pathogenic:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GLB1 c.601C>T variant is predicted to result in the amino acid substitution p.Arg201Cys. This variant was reported to be causative for GM1 Gangliosidosis (Yoshida et. al. 1991. PubMed ID: 1907800; Karimzadeh et al. 2017. PubMed ID: 28716012). Pathogenic variants in GLB1 have been associated with autosomal recessive GM1-gangliosidosis, type I (OMIM #230500), autosomal recessive GM1-gangliosidosis, type II (OMIM #230600), autosomal recessive GM1-gangliosidosis, type III (OMIM #230650), and autosomal recessive Mucopolysaccharidosis type IVB, Morquio (OMIM #253010). This variant is reported in 0.0089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

GM1 gangliosidosis type 3 Pathogenic:1

Oct 30, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Oct 30, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:1

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Uncertain	0.80	.;.;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.6
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72555360; hg19: chr3-33099713; COSMIC: COSV56561720; COSMIC: COSV56561720;