Submissions for variant NM_000512.5(GALNS):c.898+1G>A

gnomAD frequency: 0.00001  dbSNP: rs761850746

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633461	SCV000754690	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2019-09-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALNS are known to be pathogenic (PMID: 12442278). This variant has been observed as homozygous or in combination with another GALNS pathogenic variant in individuals affected with mucopolysaccharidosis IVA (PMID: 9298823, 23876334). This variant is also known as IVS8+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 528323). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change affects a donor splice site in intron 8 of the GALNS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000633461	SCV001547826	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Splicing variant in canonical site (PVS1_very strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate)
Genome-Nilou Lab	RCV000633461	SCV002045008	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000633461	SCV005380243	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-10-21	criteria provided, single submitter	clinical testing	A Homozygous variation in intron 8 of the GALNS gene. The observed variant c.898+1G>A has not been reported in the 1000 genomes database and has a MAF of 0.0005% in the gnomAD database. The in silico prediction of the variant is possibly damaging by MutationTaster2, DANN and spliceAI. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.