ClinVar

Description

Variant summary: GALNS c.871G>A (p.Ala291Thr) 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 was absent in 229188 control chromosomes. c.871G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Bunge_1997, Montao_2003, Tomatsu_2004, Bidchol_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Montao_2003). The most pronounced variant effect results in non-detectable lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 25252036, 9298823, 12721840, 15235041). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.