ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.601C>T (p.Arg201Cys) (rs72555360)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411359 SCV000487674 pathogenic Infantile GM1 gangliosidosis 2016-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000000973 SCV000487675 pathogenic GM1 gangliosidosis type 2 2016-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000410436 SCV000487676 pathogenic Gangliosidosis GM1 type 3 2016-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000411949 SCV000487677 pathogenic Mucopolysaccharidosis, MPS-IV-B 2016-10-30 criteria provided, single submitter clinical testing
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.
GeneDx RCV000256168 SCV000321710 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The R201C variant has previously been associated with type II (late infantile/juvenile) GM1-gangliosidosis (Yoshida et al. 1991; Hofer et al., 2009). Expression in Cos-1 cells found that R201C is associated with approximately 12%-8% of wild-type beta-galactosidase activity (Hofer el al., 2009; Caciotti et al. 2003). The R201C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In summary, we interpret R201C to be a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000411359 SCV000746821 pathogenic Infantile GM1 gangliosidosis 2017-12-18 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000000973 SCV000297795 pathogenic GM1 gangliosidosis type 2 2016-07-14 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000366704 SCV000443185 uncertain significance Morquio syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
OMIM RCV000000973 SCV000021123 pathogenic GM1 gangliosidosis type 2 2003-07-01 no assertion criteria provided literature only

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