Submissions for variant NM_000404.4(GLB1):c.442C>T (p.Arg148Cys)

dbSNP: rs192732174

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178094	SCV000230089	pathogenic	not provided	2013-07-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000666298	SCV000790566	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-03-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778692	SCV000915043	pathogenic	GM1 gangliosidosis	2017-10-19	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000818014	SCV000958605	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-01-13	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 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.
Baylor Genetics	RCV001331203	SCV001523191	pathogenic	Infantile GM1 gangliosidosis	2020-07-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV000666298	SCV002808688	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2022-02-23	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001331203	SCV002822850	likely pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing	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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001331203	SCV004100636	pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000778692	SCV004803937	pathogenic	GM1 gangliosidosis	2024-01-29	criteria provided, single submitter	clinical testing	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.