ClinVar Miner

Submissions for variant NM_001139.3(ALOX12B):c.71T>C (p.Leu24Pro)

gnomAD frequency: 0.00001  dbSNP: rs201575829
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509651 SCV002819736 pathogenic Lamellar ichthyosis 2022-12-03 criteria provided, single submitter clinical testing Variant summary: ALOX12B c.71T>C (p.Leu24Pro) results in a non-conservative amino acid change located in the PLAT/LH2 domain (IPR001024) 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 2.4e-05 in 251492 control chromosomes. c.71T>C has been reported in the literature as biallelic compound heterozygous genotypes in individuals affected with features of Lamellar Ichthyosis (example, Eckl_2005, Diociaiuti_2016, Hotz_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Eckl_2005). The most pronounced variant effect results in a complete loss of catalytic activity of the epidermal lipoxygenase, 12R-LOX in-vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV003238858 SCV003936375 likely pathogenic not provided 2023-06-27 criteria provided, single submitter clinical testing Observed multiple times with a second ALOX12B variant in unrelated patients with ichthyosis referred for genetic testing at GeneDx and reported in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Eckl et al., 2005; Diociaiuti et al., 2016; Hotz et al., 2021); Published functional studies demonstrate that this variant is associated with loss of enzymatic activity (Eckl et al., 2005); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26762237, 33435499, 33726816, 16116617)
Invitae RCV003238858 SCV004247823 pathogenic not provided 2023-10-07 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 24 of the ALOX12B protein (p.Leu24Pro). This variant is present in population databases (rs201575829, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 16116617, 26762237, 33435499). ClinVar contains an entry for this variant (Variation ID: 995481). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALOX12B protein function. For these reasons, this variant has been classified as Pathogenic.
Institute for Human Genetics, University Medical Center Freiburg RCV001289514 SCV001477388 pathogenic Autosomal recessive congenital ichthyosis 2 2021-01-07 no assertion criteria provided clinical testing

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