Submissions for variant NM_002076.4(GNS):c.1098+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003236507	SCV003934816	pathogenic	Mucopolysaccharidosis, MPS-III-D	2023-05-19	criteria provided, single submitter	clinical testing	Variant summary: GNS c.1098+1G>A 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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251464 control chromosomes (gnomAD). c.1098+1G>A has been reported in the literature in a homozygous individual affected with Mucopolysaccharidosis Type IIID (Sanfilippo Syndrome D) (Kaissi_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27512882). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003236507	SCV004294225	likely pathogenic	Mucopolysaccharidosis, MPS-III-D	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the GNS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNS are known to be pathogenic (PMID: 20232353). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal recessive mucopolysaccharidosis type IIID (PMID: 27512882). ClinVar contains an entry for this variant (Variation ID: 2506276). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.