Submissions for variant NM_000404.4(GLB1):c.245+1G>A

gnomAD frequency: 0.00001  dbSNP: rs778423653

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000477865	SCV000794015	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685614	SCV000813099	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 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 (rs778423653, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with GM1-gangliosidosis (PMID: 15365997, 16941474, 17221873). ClinVar contains an entry for this variant (Variation ID: 417873). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 17221873). 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	RCV001175540	SCV001339161	pathogenic	GM1 gangliosidosis	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.245+1G>A 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: Four predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions demonstrating the variant gives rise to at least one aberrant transcript skipping exon 2 and leading to a premature termination codon (Caciotti_2007). The variant allele was found at a frequency of 8e-06 in 249272 control chromosomes (gnomAD). c.245+1G>A has been reported in the literature, in homozygous or compound heterozygous state, in multiple individuals affected with GM1 gangliosidosis (e.g. Caciotti_2007, Georgiou_2004, Hofer_2010, Santamaria_2006). These data indicate that the variant is very likely to be associated with disease. Testing of cells from homozygous patients revealed reduced (or absent) levels of both GLB1 and EBP mRNA expression and absent (0%) beta-Gal enzyme activity (e.g. Caciotti_2007, Hofer_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000477865	SCV002811471	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV004591410	SCV005080583	pathogenic	not provided	2023-12-10	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: 25525159, 33737400, 15365997, 17221873, 18184943, 16941474)
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477865	SCV000536738	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2016-12-12	no assertion criteria provided	research