Submissions for variant NM_001139.3(ALOX12B):c.1463G>A (p.Arg488His)

gnomAD frequency: 0.00001  dbSNP: rs763468558

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222692	SCV002500470	pathogenic	Lamellar ichthyosis	2022-03-18	criteria provided, single submitter	clinical testing	Variant summary: ALOX12B c.1463G>A (p.Arg488His) results in a non-conservative amino acid change in 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 4e-06 in 251322 control chromosomes (gnomAD). c.1463G>A has been reported in the literature in multiple individuals affected with autosomal recessive congenital ichthyoses, including several homozygotes (Eckl_2005, Seidl-Philipp_2020) and at least one compound heterozygote (Israeli_2013). These data indicate that the variant is very likely to be associated with disease. Eckl et al (2005) also examined the variant protein's ability to convert arachidonic acid and determined that the variant protein had complete loss of enzymatic activity. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003405498	SCV004109813	pathogenic	ALOX12B-related disorder	2023-01-31	criteria provided, single submitter	clinical testing	The ALOX12B c.1463G>A variant is predicted to result in the amino acid substitution p.Arg488His. This variant has been previously reported in the homozygous or compound heterozygous state in individuals with autosomal recessive congenital ichthyosis (Eckl et al. 2005. PubMed ID: 16116617; Ashoor et al. 2006. PubMed ID: 16792775; Figure 2A, Hotz et al. 2021. PubMed ID: 33435499; Saat et al. 2022. PubMed ID: 35734965; Israeli et al. 2013. PubMed ID: 23621129). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7979562-C-T). This variant is interpreted as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001289523	SCV005416325	pathogenic	Autosomal recessive congenital ichthyosis 2		criteria provided, single submitter	clinical testing	PP3_Moderate+PM2_Supporting+PM3_VeryStrong
Institute for Human Genetics, University Medical Center Freiburg	RCV001289523	SCV001477397	pathogenic	Autosomal recessive congenital ichthyosis 2	2021-01-07	no assertion criteria provided	clinical testing