ClinVar Genomic variation as it relates to human health

Variant summary: GALNS c.239C>T (p.Ser80Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain 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 4e-06 in 247532 control chromosomes. c.239C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A, Tomatsu_2005, Pollard_2013, Tapiero-Rodriguez_2018). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal expression/activity (Tomatsu_2006, Tapiero-Rodriguez_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

In vitro and vivo 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)

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 80 of the GALNS protein (p.Ser80Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9375852, 22976768, 25545067, 29731656). ClinVar contains an entry for this variant (Variation ID: 521930). 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: 9375852). For these reasons, this variant has been classified as Pathogenic.

The GALNS c.239C>T variant is predicted to result in the amino acid substitution p.Ser80Leu. This variant was reported in homozygous and compound heterozygous state in multiple individuals with Mucopolysaccharidosis IVA (Tomatsu et al. 1997. PubMed ID: 9375852; Pachajoa et al. 2021. PubMed ID: 34542925; Pollard et al. 2012. PubMed ID: 22976768; Tapiero-Rodriguez et al. 2018. PubMed ID: 29731656). In vitro and in vivo studies show that this variant results in significantly reduced enzymatic activity (Tomatsu et al. 1997. PubMed ID: 9375852; Tapiero-Rodriguez et al. 2018. PubMed ID: 29731656). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-88909119-G-A). This variant is interpreted as likely pathogenic.

The observed missense variant c.239C>T(p.Ser80Leu) in GALNS gene has been reported previously in homozygous, compound heterozygous state in individuals with mucopolysaccharidosis IVA (Tapiero-Rodriguez SM, et al., 2018, Pollard LM, et al., 2013). Experimental studies have shown that this missense change affects GALNS function (Tomatsu S, et al., 1997). The c.239C>T variant has 0.0004% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Serine at position 80 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ser80Leu in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.