Submissions for variant NM_000512.5(GALNS):c.422+2dup

dbSNP: rs2143004586

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578506	SCV001547687	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Absent from gnomAD v2.1.1 (PM2_moderate)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800987	SCV005422490	uncertain significance	not specified	2024-10-10	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.422+2dupT 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: 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 251020 control chromosomes (gnomAD). c.422+2dupT (also known as c.422+2_+3insT in the literature) has been reported in the literature in two siblings affected with severe Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (example: Dung_2013). 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 has been ascertained in the context of this evaluation (PMID: 23876334). ClinVar contains an entry for this variant (Variation ID: 1048401). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.