Submissions for variant NM_000512.5(GALNS):c.899-1G>C

gnomAD frequency: 0.00001  dbSNP: rs745523154

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	RCV001578585	SCV001547828	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	Splicing variant in canonical site (PVS1_very strong); in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509670	SCV002819847	pathogenic	Morquio syndrome	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.899-1G>C 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. At least one publication (Carraresi_2008) reported experimental evidence confirming this prediction, by demonstrating in patient derived fibroblasts that the variant results in two aberrantly spliced transcripts with exon 9 skipping (both causing a frame-shift, introducing a premature stop codon, however both mRNAs seemed to escape nonsense-mediated decay (NMD)). The variant allele was found at a frequency of 4e-06 in 248806 control chromosomes (gnomAD). c.899-1G>C has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Carraresi_2008, Morrone_2014, Caciotti_2015). These data indicate that the variant is likely to be associated with disease. At least one publication also reported experimental evidence demonstrating an impact on protein function, i.e. showing that GALNS enzyme activity was completely absent in leukocytes derived from a patient homozygous for the variant of interest (Caciotti_2015). One ClinVar submitter (evaluation after 2014) has cited the variant and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578585	SCV004297065	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 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. This variant is present in population databases (rs745523154, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Morquio A (PMID: 18710657). ClinVar contains an entry for this variant (Variation ID: 1048482). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18710657). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.