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

Total submissions: 8

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