Submissions for variant NM_000404.4(GLB1):c.1480-2A>G

gnomAD frequency: 0.00001  dbSNP: rs587776526

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000790562	SCV000929914	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2019-01-01	criteria provided, single submitter	literature only	PVS1: splicing site (-2). PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in ExAC
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049270	SCV001213314	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the GLB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587776526, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with GLB1-related conditions (PMID: 10737981, 21497194, 25557439). ClinVar contains an entry for this variant (Variation ID: 946). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10737981). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251276	SCV001426802	pathogenic	GM1 gangliosidosis	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1480-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 splicing donor site. Four predict the variant abolishes a 3 acceptor site. In agreement with this, at least one publication reports experimental evidence that this variant affects mRNA splicing (Morrone_2000). The variant allele was found at a frequency of 1.2e-05 in 245574 control chromosomes (gnomAD). c.1480-2A>G has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with GM1 Gangliosidosis (Morrone_2000, Santamaria_2006, Utz_2015, Caciotti_2011) and in at least one individual (compound heterozygous) with MorquioB (Caciotti_2011). Most of the GM1 Gangliosidosis patients were of infantile phenotype. These data indicate that the variant is very likely to be associated with disease. Enzymatic activity from patient derived (who were homozygous for this variant) fibroblasts and leukocytes were found to have very low activity (Morrone_2000, Santamaria_2006). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002243610	SCV002512898	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10737981, 16941474, 30809705, 25557439, 21497194, 25525159)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470702	SCV002767815	pathogenic	Infantile GM1 gangliosidosis	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type I GM1-gangliosidosis (MIM#230500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sequencing of cDNA obtained from patient’s RNA revealed the intronic retention of 28bp, leading to a frameshift and premature termination codon (PMID: 10737981). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been reported as pathogenic in at least five patients, in a homozygous or compound heterozygous state, with either GM1-gangliosidosis, type I (MIM#230500) or mucopolysaccharidosis type IVB (Morquio) (MIM#253010) (ClinVar, HGMD, PMIDs: 10737981, 16941474, 21497194, 30809705). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The enzymatic activity of beta-galactosidase was reduced to 1% of controls in patient cells (PMID: 10737981). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000404.3:c.1445G>A; p.(Arg482His)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited [(LABID/by trio analysis)]. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002496221	SCV002808763	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2024-04-17	criteria provided, single submitter	clinical testing
OMIM	RCV000000996	SCV000021146	pathogenic	GM1-gangliosidosis, type I, with cardiac involvement	2000-01-01	no assertion criteria provided	literature only