Submissions for variant NM_000404.4(GLB1):c.442C>T (p.Arg148Cys) (rs192732174)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666298	SCV000790566	likely pathogenic	GM1 gangliosidosis type 2; Gangliosidosis GM1 type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-03-29	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000178094	SCV000230089	pathogenic	not provided	2013-07-08	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,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	2018-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 148 of the GLB1 protein (p.Arg148Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs192732174, ExAC 0.003%). This variant has been observed in several individuals affected with GM1 gangliosidosis or mucopolysaccharidosis type IV (PMID: 15986423, 23151865, 17221873, 25936995). ClinVar contains an entry for this variant (Variation ID: 92907). Experimental studies have shown that this missense change abrogates GLB1 enzymatic activity (PMID: 17221873). The observation of one or more missense substitutions at this codon (p.Arg148Cys and p.Arg148Ser) in affected individuals suggests that this may be a clinically significant residue (PMID: 10839995, 15986423, 23151865, 17221873, 25936995). For these reasons, this variant has been classified as Pathogenic.