Submissions for variant NM_000404.4(GLB1):c.1144-2A>G

dbSNP: rs1553607014

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673337	SCV000798526	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2018-03-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071947	SCV001237283	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2020-01-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with GM1 gangliosidosis (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557226). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the GLB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387908	SCV004100076	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B	2023-09-22	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1144-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Three predict the variant creates a 3' acceptor site. One predict the variant strengthens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247058 control chromosomes. c.1144-2A>G has been reported in the literature in individuals affected with Skeletal dysplasia (Uttarilli_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30408610). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.