Submissions for variant NM_000404.4(GLB1):c.902C>T (p.Ala301Val)

gnomAD frequency: 0.00001  dbSNP: rs750531880

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418628	SCV000520957	pathogenic	not provided	2017-02-02	criteria provided, single submitter	clinical testing	The c.902 C>T pathogenic variant in the GLB1 gene has been reported previously with another GLB1 variant in multiple unrelated individuals with GM1-gangliosidosis (Santamaria et al., 2006; Yang et al., 2010; Hofer et al., 2010). Functional studies have shown that the c.902 C>T variant is associated with significantly reduced beta-galactosidase activity (Yang et al., 2010). The c.902 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.902 C>T may create a cryptic splice donor site in exon 8, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.902 C>T change in this individual is unknown. If c.902 C>T does not alter splicing, it will result in the A301V missense change. The A301V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.902 C>T as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244569	SCV001417798	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 301 of the GLB1 protein (p.Ala301Val). This variant is present in population databases (rs750531880, gnomAD 0.002%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 16941474, 20175788, 20409738, 20920281). This variant is also known as r.901_914del. ClinVar contains an entry for this variant (Variation ID: 381567). 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: 16941474, 20175788). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000418628	SCV002024832	pathogenic	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330669	SCV004037683	pathogenic	GM1 gangliosidosis	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.902C>T (p.Ala301Val) 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' splicing donor site, and one predicts the variant strengthens this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that inhibition of nonsense-mediated decay in a patient with the variant allowed detection of the transcript, which contains a deletion of 14 nucleotides at the 3' end of exon 8 (Santamaria_2006). The variant allele was found at a frequency of 8e-06 in 249468 control chromosomes (gnomAD). c.902C>T has been reported in the literature in individuals affected with GM1 Gangliosidosis (Yang_2010, Hofer_2010, Santamaria_2006, Arash-Kaps_2019, King_2020), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding no residual enzymatic activity in transfected cells (Yang_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20920281, 20175788, 16941474, 31761138, 33240792). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004532999	SCV004117296	pathogenic	GLB1-related disorder	2023-01-04	criteria provided, single submitter	clinical testing	The GLB1 c.902C>T variant is predicted to result in the amino acid substitution p.Ala301Val. This variant has been reported in the compound heterozygous state in individuals with Gangliosidosis GM1, including one sibling pair (Hofer et al. 2010. Table 1 PubMed ID: 20175788; Yang et al. 2010. PubMed ID: 20920281; Arash-Kaps et al. 2019. Table III PubMed ID: 31761138; King et al. 2020. Table 1 PubMed ID: 33240792; Santamaria et al. 2006. PubMed ID: 16941474). This variant has been reported to affect splicing and to significantly reduce enzyme activity in vitro compared to control (Santamaria et al. 2006. PubMed ID: 16941474; Hofer et al. 2010. Table 3 PubMed ID: 20175788; Yang et al. 2010. PubMed ID: 20920281). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-33093387-G-A). Taken together, this variant is interpreted as pathogenic.
Counsyl	RCV000670128	SCV000794945	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B	2017-10-23	no assertion criteria provided	clinical testing