ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1577dup (p.Trp527fs) (rs794729217)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627406 SCV000748400 pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing The c.1577dupG variant in the GLB1 gene has been reported previously using alternate nomenclature (1622-1627insG) in association with autosomal recessive GM1-gangliosidosis type I (Silva et al., 1999). This variant is common in individuals from Brazil, having been identified in 42.5% of alleles from affected individuals in one study (Silva et al., 1999). The c.1577dupG variant causes a frameshift starting with codon Tryptophan 527, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Trp527LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1577dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1577dupG as a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000784901 SCV000923441 pathogenic GLB1-Related Disorders 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV000798976 SCV000938621 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-09-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp527Leufs*5) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with GM1 gangliosidosis (PMID: 10338095, 15986423). ClinVar contains an entry for this variant (Variation ID: 202191). Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000987139 SCV001136360 pathogenic GM1 gangliosidosis type 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000627406 SCV001248011 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260322 SCV001437247 pathogenic GM1 gangliosidosis 2020-09-17 criteria provided, single submitter clinical testing Variant summary: GLB1 c.1577dupG (p.Trp527LeufsX5) 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 8.1e-06 in 247798 control chromosomes (gnomAD). c.1577dupG has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with GM1 Gangliosidosis (e.g. Silva_1999, Arash-Kaps_2019). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000184037 SCV000236568 pathogenic Infantile GM1 gangliosidosis 2013-11-26 no assertion criteria provided clinical testing
GeneReviews RCV000184037 SCV001821205 pathogenic Infantile GM1 gangliosidosis 2021-04-19 no assertion criteria provided literature only High prevalence in Brazilian population; associated with GM1 infantile form

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