Submissions for variant NM_000404.4(GLB1):c.1077del (p.Val360fs)

dbSNP: rs727503952

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173999	SCV000225218	pathogenic	not provided	2013-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV001035980	SCV001199320	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 167146). This variant is also known as p.K359Kfs*23. This premature translational stop signal has been observed in individuals with GM1 gangliosidosis (PMID: 20175788, 25936995). This variant is present in population databases (rs727503952, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Val360Tyrfs*23) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192990	SCV001361488	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1077delA (p.Val360TyrfsX23) 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. Truncations downstream of this position have been classified as pathogenic by other laboratories (eg. c.1174_1175delCT/p.Leu392Valfs, c.1188dupG/p.Pro397Alafs). The variant allele was found at a frequency of 8.2e-06 in 243488 control chromosomes. c.1077delA has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B, Hofer_2010, Bidchol_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001192990	SCV002570296	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2022-02-17	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002291499	SCV002583284	pathogenic	Infantile GM1 gangliosidosis	2022-09-30	criteria provided, single submitter	clinical testing	The variant has shown a homozygous status for c.1221del (p.Val408TyrfsTer23) in exon 12 of the GLB1 gene. This variant is not reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is disease causing mutation Taster2.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470776	SCV002767566	pathogenic	GM1 gangliosidosis	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous frameshift deletion variant was identified, NM_000404.3(GLB1):c.1077del in exon 11 of 16 of the GLB1 gene. This deletion is predicted to cause a frameshift starting at position 360, NP_000395.2(GLB1):p.(Val360Tyrfs*23), resulting in a loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0008% (2 heterozygotes; 0 homozygotes), observed within the South Asian population only. The variant has previously been reported as pathogenic in patients with GM1-gangliosidosis, and has been observed in cis with a missense variant (NM_000404.3(GLB1):c.1071T>G; NP_000395.2(GLB1):p.(Phe357Leu)) (ClinVar, Hofer, D. et al. (2012), Bidchol, A. et al. (2015), Uttarilli, A. et al. (2019)). Other variants predicted to cause NMD have also been reported as pathogenic in individuals with this condition (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002291499	SCV004047844	pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing	The c.1077del (p.Val360TyrfsTer23) frameshift variant in GLB1 gene has been observed in several individuals affected with GM1 gangliosidosis (Hofer et al., 2010; Bidchol et al., 2015). This variant is reported with the allele frequency (0.0008%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Valine 360, changes this amino acid to Tyrosine residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Val360TyrfsTer23. Loss-of-function variants in GLB1 are known to be pathogenic (Brunetti-Pierri and Scaglia, 2008). For these reasons, this variant has been classified as Pathogenic.