ClinVar Genomic variation as it relates to human health

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; 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)

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000528320, PMID:24726177). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:16287098). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.977>=0.6, 3CNET: 0.791>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000260). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces leucine with arginine at codon 36 of the GALNS protein (p.Leu36Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed as homozygous in several individuals affected with mucopolysaccharidosis IVA, and it has been found in trans with a pathogenic GALNS variant in an affected individual (PMID: 24726177, 25252036, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 528320). This variant is present in population databases (rs755832705, ExAC 0.04%).

The missense variant c.107T>G (p.Leu36Arg) in the GALNSgene has been reported previously in homozygous and compound heterozygous state in multiple individuals affected with Mucopolysaccharidosis IVA syndrome (Sheth et al., 2022; Bidchol et al., 2014). This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic. The amino acid Leucine at position 36 is changed to an Arginine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Leu36Arg in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.