Submissions for variant NM_001139.3(ALOX12B):c.410T>A (p.Ile137Asn)

dbSNP: rs397514530

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487263	SCV000568675	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	The I137N variant in the ALOX12B gene has been reported previously in a patient with ichthyosiform erythroderma who was also heterozygous for a second variant (Harting et al., 2008). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I137N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret I137N as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478981	SCV004223356	uncertain significance	not specified	2023-11-01	criteria provided, single submitter	clinical testing	Variant summary: ALOX12B c.410T>A (p.Ile137Asn) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250776 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.410T>A has been reported in the literature in one individual affected with autosomal recessive congenital ichthyoses (Harting_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19131948, 18347291, 33435499, 36003334). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000032740	SCV000056504	pathogenic	Autosomal recessive congenital ichthyosis 2	2008-03-01	no assertion criteria provided	literature only