Submissions for variant NM_000404.4(GLB1):c.442C>A (p.Arg148Ser) (rs192732174)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666897	SCV000791267	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-05-15	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000727559	SCV000854793	pathogenic	not provided	2018-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780304	SCV000917466	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2018-05-11	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.442C>A (p.Arg148Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase 35 catalytic domain 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 4.3e-05 in 276992 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing GM1 gangliosidosis (4.3e-05 vs 2.00e-03), allowing no conclusion about variant significance. The variant, c.442C>A, has been reported in the literature in several individuals affected with GM1 gangliosidosis (Zhang_2000, Hofer_2010, Nestrasil_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein maturation and enzyme activity, with both being significantly reduced in the presence of the variant (Zhang_2000). Additionally, other variants at the Arg148 residue have been reported as associated with disease (p.Arg148Cys and p.Arg148His), suggesting that this codon is important for function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001055679	SCV001220079	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2020-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 148 of the GLB1 protein (p.Arg148Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs192732174, ExAC 0.006%). This variant has been observed in individuals affected with GM1 gangliosidosis (PMID: 25600812, 20175788, 10839995). ClinVar contains an entry for this variant (Variation ID: 551757). This variant has been reported to affect GLB1 protein function (PMID: 10839995). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg148 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15986423, 23151865, 17221873, 25936995, 17221873). 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.
GeneDx	RCV000727559	SCV001871370	pathogenic	not provided	2021-08-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate R148S leads to a decrease in enzymatic activity (Zhang et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20175788, 10839995, 33240792, 16674934, 29352662, 15365997, 16763919, 25600812, 18353697, 22784478, 10841810, 24024947)
GenomeConnect - GM1	RCV001175301	SCV001338923	not provided	GM1 gangliosidosis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-25-2014 by Lab or GTR ID 239772. 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.