ClinVar

Description

Variant summary: MANBA c.960+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. cDNA sequencing shows mis-splicing results in a four-base (ATAA) insertion between exons 7 and 8, which replaces the C-terminal sequence of the protein with an aberrant and truncated peptide of four residues (Uchino_2003). The variant allele was found at a frequency of 1.2e-05 in 248618 control chromosomes. c.960+1G>A has been reported in the literature in one homozygous individual affected with Beta-Mannosidosis (Uchino_2003). The activity of b-mannosidase in plasma from the affected homozygous individual was very low, at about 2% of the value in healthy controls, suggesting the variant impacts protein function (Uchino_2003). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.