Submissions for variant NM_000512.5(GALNS):c.1003-3C>G

dbSNP: rs760239741

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578534	SCV001547872	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); absent from gnomAD v2.1.1 (PM2_moderate)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331132	SCV004038293	pathogenic	Morquio syndrome	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.1003-3C>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site and two predict it weakens the site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182508 control chromosomes (gnomAD). c.1003-3C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A; Bidchol_2014, Uttarilli_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25252036, 30408610). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001578534	SCV004171369	uncertain significance	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578534	SCV004297063	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1048432). This variant is also known as IVS9-3C>G. This variant has been observed in individuals with mucopolysaccharidosis type IVA (PMID: 25252036). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the GALNS gene. It does not directly change the encoded amino acid sequence of the GALNS protein. It affects a nucleotide within the consensus splice site.