Submissions for variant NM_000404.4(GLB1):c.601C>T (p.Arg201Cys)

gnomAD frequency: 0.00006  dbSNP: rs72555360

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000000973	SCV000297795	pathogenic	GM1 gangliosidosis type 2	2016-07-14	criteria provided, single submitter	research
GeneDx	RCV000256168	SCV000321710	pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000269582	SCV000443186	likely pathogenic	GM1 gangliosidosis	2017-04-28	criteria provided, single submitter	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.
Dr. Faghihi's Medical Genetic Center	RCV000000973	SCV000537312	pathogenic	GM1 gangliosidosis type 2	2017-01-20	criteria provided, single submitter	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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000411359	SCV000746821	pathogenic	Infantile GM1 gangliosidosis	2017-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV001208622	SCV001380021	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-12-01	criteria provided, single submitter	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). 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.
OMIM	RCV000000973	SCV000021123	pathogenic	GM1 gangliosidosis type 2	2003-07-01	no assertion criteria provided	literature only
Counsyl	RCV000411359	SCV000487674	pathogenic	Infantile GM1 gangliosidosis	2016-10-30	no assertion criteria provided	clinical testing
Counsyl	RCV000000973	SCV000487675	pathogenic	GM1 gangliosidosis type 2	2016-10-30	no assertion criteria provided	clinical testing
Counsyl	RCV000410436	SCV000487676	pathogenic	GM1 gangliosidosis type 3	2016-10-30	no assertion criteria provided	clinical testing
Counsyl	RCV000411949	SCV000487677	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2016-10-30	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000256168	SCV001953312	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256168	SCV001964556	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - GM1	RCV000000973	SCV002047667	not provided	GM1 gangliosidosis type 2		no assertion provided	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.