Submissions for variant NM_000512.5(GALNS):c.935C>G (p.Thr312Ser)

gnomAD frequency: 0.00002  dbSNP: rs118204446

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193737	SCV001362799	pathogenic	Morquio syndrome	2019-12-11	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.935C>G (p.Thr312Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250636 control chromosomes (gnomAD). c.935C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A)(Yamada_1998). Authors indicate the variant causes a mild phenotype. These data indicate that the variant is very likely to be associated with disease. Functional analysis performed by Yamada_1998 found the variant to produce 15% normal activity. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000748	SCV001547846	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate); 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); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000748	SCV001591347	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 312 of the GALNS protein (p.Thr312Ser). This variant is present in population databases (rs118204446, gnomAD 0.004%). This missense change has been observed in individuals with MPS IVA (PMID: 9521421, 15235041). ClinVar contains an entry for this variant (Variation ID: 713). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALNS function (PMID: 9521421, 10814710). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000000748	SCV002045006	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000000748	SCV005641470	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-06-15	criteria provided, single submitter	clinical testing
OMIM	RCV000000748	SCV000020898	pathogenic	Mucopolysaccharidosis, MPS-IV-A	1998-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000000748	SCV000086809	not provided	Mucopolysaccharidosis, MPS-IV-A		no assertion provided	literature only