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

dbSNP: rs794729217

Total submissions: 9

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	2023-12-30	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. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs794729217, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with GM1 gangliosidosis (PMID: 10338095, 15986423, 16941474, 17309651, 25936995). This variant is also known as c.1622_1627insG,1606_1611insG, c.1577 1578insG, or c.1572_1577insG. ClinVar contains an entry for this variant (Variation ID: 202191). 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 Center for Human Genetics 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137707	SCV003807647	pathogenic	GM1 gangliosidosis type 3	2022-10-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 moderated, PM3 very strong
Mendelics	RCV000184037	SCV000236568	pathogenic	Infantile GM1 gangliosidosis	2013-11-26	no assertion criteria provided	clinical testing
GeneReviews	RCV000184037	SCV001821205	not provided	Infantile GM1 gangliosidosis		no assertion provided	literature only	High prevalence in Brazilian population; associated with GM1 infantile form