ClinVar

Description

The p.Ser258Leu variant in ALG1 has been reported in at least 10 homozygous and 14 compound heterozygous individuals with a congenital disorder of glycosylation (Grubenmann 2004, Schwarz 2004, Kranz 2004, Harshman 2016, Ng 2016, Park 2016, Barba 2016, and Bowling 2017), and has also been reported in ClinVar (Variation ID#4724). In vitro functional studies provide evidence that the p.Ser258ZLeu var iant impacts the protein (Grubenmann 2004, Schwarz 2004, Kranz 2004, and Ng 2016 ). This variant has been identified in 0.05% (67/126078) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs28939378). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, although additional studies are required to fully establish its c linical significance, the p.Ser258Leu variant is pathogenic for congenital disor ders of glycosylation in an autosomal recessive manner based on functional studi es and its occurrence in individuals with this disease.