Submissions for variant NM_000512.5(GALNS):c.871G>T (p.Ala291Ser)

dbSNP: rs118204448

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420010	SCV000517439	pathogenic	not provided	2015-06-03	criteria provided, single submitter	clinical testing	The A291S variant was found at a frequency of 5.88% in Indian patients with Morquiosyndrome (Bidchol et al. 2014). Individuals who were homozygous for A291S were reported to have asevere phenotype (Bidchol et al. 2014). Therefore, we interpret A291S as a pathogenic variant.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578578	SCV001547818	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	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_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV001578578	SCV002044948	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001578578	SCV004238207	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526672	SCV005040249	pathogenic	Morquio syndrome	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.871G>T (p.Ala291Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.871G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.871G>A, p.Ala291Thr) has been classified as pathogenic by our lab, supporting a critical relevance of this residue to GALNS protein function. The following publications have been ascertained in the context of this evaluation (PMID: 25252036, Ullah_Turk J Biol_2017 (No PMID)). ClinVar contains an entry for this variant (Variation ID: 379921). Based on the evidence outlined above, the variant was classified as pathogenic.