ClinVar Genomic variation as it relates to human health

The heterozygous c.1137+200_1137+205del variant in ASNS was identified by our study, in the compound heterozygous state along with a likely pathogenic variant in one individual with Lennox-Gastaut syndrome, infantile spasms, microcephaly, hypoplasia/partial agenesis of the corpus callosum, delayed myelination, and hypotonia (Broad Institute Rare Genomes Project). Trio genome analysis revealed that this variant was in trans with a likely pathogenic variant. The c.1137+200_1137+205del variant in ASNS has not been previously reported in individuals with asparagine synthetase deficiency. This variant was absent from large population studies. RNAseq analysis performed on affected tissue showed evidence of altering splicing with retention of intron 9 (Broad Rare Genomes Project). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive asparagine synthetase deficiency. ACMG/AMP Criteria applied: PS3, PM2_Supporting, PM3 (Richards 2015).

The c.1137+200_1137+205del variant in ASNS has not been reported in the literature in individuals with asparagine synthetase deficiency but was identified by the Broad Institute Rare Genomes Project in compound heterozygosity with a likely pathogenic variant in a child with Lennox-Gastaut syndrome, infantile spasms, microcephaly, hypoplasia/partial agenesis of the corpus callosum, and hypotonia. It was absent from large population studies. This variant is located in intron 9 and is distant from the splice consensus region. However, RNAseq analysis performed on a blood sample from an affected individual carrying this variant shows evidence of intron 9 retention (Broad Institute Rare Genomes Project), supporting computational predictions suggesting that this variant may create a novel splice acceptor. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive asparagine synthetase deficiency. ACMG/AMP Criteria applied: PS3, PM3, PM2_Supporting.