Submissions for variant NM_000512.5(GALNS):c.346G>A (p.Gly116Ser)

dbSNP: rs1444754604

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193131	SCV001361768	pathogenic	Morquio syndrome	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.346G>A (p.Gly116Ser) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251078 control chromosomes (gnomAD). c.346G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Aldeeri_2014, Bidchol_2014, Caciotti_2015, Dung_2014, Tomatsu_2004). Several of these individuals presented with severe phenotype. These data indicate that the variant is very likely to be associated with disease. Tomatsu et al (2004) reports two homozygous patients whose enzymatic activity was less than 1% of normal control. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578373	SCV001547667	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1_supporting); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV001578373	SCV002045029	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV001578373	SCV002239448	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 116 of the GALNS protein (p.Gly116Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15309681). ClinVar contains an entry for this variant (Variation ID: 928751). 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%. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003908434	SCV004719610	pathogenic	GALNS-related condition	2024-01-19	criteria provided, single submitter	clinical testing	The GALNS c.346G>A variant is predicted to result in the amino acid substitution p.Gly116Ser. This variant has been reported in the presumed compound heterozygous and homozygous states in multiple individuals with mucopolysaccharidosis IVa (MPS IVa) (Tomatsu et al. 2004. PubMed ID: 15309681; Dũng et al. 2013. PubMed ID: 23876334; Table S5, Caciotti et al. 2015. PubMed ID: 25545067; Tüysüz et al. 2019. PubMed ID: 30980944) and has been observed to co-segregate with disease in a family tested at PreventionGenetics (internal data). In vitro assays performed with cell cultures from homozygous individuals have shown this variant leads to a complete loss of enzymatic activity (Tomatsu et al. 2004. PubMed ID: 15309681; Bidchol et al. 2014. PubMed ID: 25252036). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. A different missense variant at the same amino acid position (p.Gly116Val) has also been reported as disease-causing in patients with MPS IVa (Morrone et al. 2014. PubMed ID: 24726177). Taken together, this variant is interpreted as pathogenic.