Submissions for variant NM_000512.5(GALNS):c.423-1G>A

dbSNP: rs2143002474

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578507	SCV001547688	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Splicing variant in canonical site (PVS1_very strong); absent from gnomAD v2.1.1 (PM2_moderate)
Invitae	RCV001578507	SCV004296418	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the GALNS gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GALNS protein in which other variant(s) (p.Trp520*) have been determined to be pathogenic (PMID: 24035930, 24726177). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 9290256). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1048402). This variant is also known as IVS 4(-1) G>A. Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive mucopolysaccharidosis IVA (PMID: 9290256). This variant is not present in population databases (gnomAD no frequency).
Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	RCV001578507	SCV004012880	association not found	Mucopolysaccharidosis, MPS-IV-A		no assertion criteria provided	research