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); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)

Variant summary: GALNS c.245C>T (p.Ser82Leu) 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. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 242556 control chromosomes (gnomAD). c.245C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A, e.g. Wang_2010, Dung_2013, Bidchol_2014). 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. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, two as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The missense c.245C>T(p.Ser82Leu) variant, lying in splice region of GALNS gene has been reported previously in compound heterozygous and homozygous states in multiple individuals affected with Mucopolysaccharidosis IVA (Dũng VC, et. al., 2013; Zanetti et. al., 2021; Stranneheim et. al., 2021). This p.Ser82Leu variant is present with an allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging , SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position on GALNS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 82 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. However, functional studies are required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 82 of the GALNS protein (p.Ser82Leu). This variant is present in population databases (rs371429653, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 20574428, 23876334). ClinVar contains an entry for this variant (Variation ID: 93175). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.