Submissions for variant NM_001139.3(ALOX12B):c.1642C>T (p.Arg548Trp)

gnomAD frequency: 0.00003  dbSNP: rs397514532

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414417	SCV000490401	likely pathogenic	not provided	2018-07-05	criteria provided, single submitter	clinical testing	The R548W variant in the ALOX12B gene has been reported previously in combination with another ALOX12B variant in individuals with congenital ichthyosiform erythroderma, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Harting et al., 2008; Israeli et al., 2013). The R548W variant is observed in 7/126,666 (0.0055%) alleles from individuals of non-Finnish European background and 8/277,126 (0.0029%) total alleles in large population cohorts (Lek et al., 2016). The R548W 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R548W as a likely pathogenic variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626762	SCV000747465	pathogenic	Congenital ichthyosiform erythroderma; Congenital nonbullous ichthyosiform erythroderma	2017-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000414417	SCV001248907	pathogenic	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032743	SCV001526510	likely pathogenic	Autosomal recessive congenital ichthyosis 2		criteria provided, single submitter	clinical testing
Invitae	RCV000414417	SCV002225035	pathogenic	not provided	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 548 of the ALOX12B protein (p.Arg548Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs397514532, ExAC 0.006%). This variant has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 23621129, 31953843). ClinVar contains an entry for this variant (Variation ID: 39545). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509181	SCV002819392	pathogenic	Lamellar ichthyosis	2022-12-09	criteria provided, single submitter	clinical testing	Variant summary: ALOX12B c.1642C>T (p.Arg548Trp) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes. c.1642C>T has been reported in the literature as a biallelic homozygous and compound heterozygous genotype in multiple individuals affected with features of Autosomal Recessive Lamellar Ichthyosis (example, Harting_2008, Israeli_2013, Cheng_2020, Srinivas_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000032743	SCV000056507	pathogenic	Autosomal recessive congenital ichthyosis 2	2008-03-01	no assertion criteria provided	literature only
Institute for Human Genetics, University Medical Center Freiburg	RCV000032743	SCV001477406	pathogenic	Autosomal recessive congenital ichthyosis 2	2021-01-07	no assertion criteria provided	clinical testing