Submissions for variant NM_000404.4(GLB1):c.2009_2010del (p.Lys670fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002720675	SCV003005138	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the GLB1 gene (p.Lys670Argfs*51). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the GLB1 protein and extend the protein by 42 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with clinical features of GM1-gangliosidosis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1961404). This variant disrupts a region of the GLB1 protein in which other variant(s) (p.Val677Gly) have been observed in individuals with GLB1-related conditions (PMID: 33558080). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324044	SCV004028686	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.2009_2010delAA (p.Lys670ArgfsX51) causes a frameshift which results in an extension of the protein. The variant was absent in 249478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2009_2010delAA in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.