ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.245+1G>A (rs778423653)

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Total submissions: 4
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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
Invitae RCV000685614 SCV000813099 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-05-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the GLB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs778423653, ExAC 0.01%). This variant has been observed in several individuals affected with GM1-gangliosidosis (PMID: 15365997, 17221873, 16941474). ClinVar contains an entry for this variant (Variation ID: 417873). Experimental studies have shown that this splicing variant causes aberrant splicing (PMID: 17221873). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
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

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