Submissions for variant NM_000404.4(GLB1):c.1369C>T (p.Arg457Ter)

gnomAD frequency: 0.00001  dbSNP: rs72555359

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667074	SCV000791469	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-05-19	criteria provided, single submitter	clinical testing
Invitae	RCV001058421	SCV001222988	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg457*) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs72555359, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with GM1 gangliosidosis (PMID: 1909089, 25936995, 28976722, 30548430). ClinVar contains an entry for this variant (Variation ID: 924). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174734	SCV001338023	pathogenic	GM1 gangliosidosis	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1369C>T (p.Arg457X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 249532 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in individuals affected with GM1 gangliosidosis (e.g. Nishimoto_1991, Santamaria_2007, Matalonga_2015). These data indicate that the variant is likely to be associated with disease. Cells expressing the variant were shown to have indetectable levels of acid beta-galactosidase enzymatic activity (Nishimoto_1991). One Clin Var submitter (evaluation after 2014 ) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000000972	SCV001810449	pathogenic	Infantile GM1 gangliosidosis	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781153	SCV002024828	pathogenic	not provided	2020-09-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001781153	SCV003916417	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	GLB1: PM3:Strong, PVS1:Strong, PM2, PP4
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000000972	SCV004023295	pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing
OMIM	RCV000000972	SCV000021122	pathogenic	Infantile GM1 gangliosidosis	1991-09-01	no assertion criteria provided	literature only