ClinVar

Description

Variant summary: ALOX12B c.1562A>G (p.Tyr521Cys) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251486 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALOX12B causing Lamellar Ichthyosis (0.00019 vs 0.0009), allowing no conclusion about variant significance. c.1562A>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Lamellar Ichthyosis (example, Pigg_2016, Eckl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific traceable experimental evidence demonstrating an impact on protein function has been reported. Although one study reported no enzyme activity, the primary data supporting this evidence were not presented (Eckl_2005). Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic.