rs147149459
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBS1_Supporting
The NM_021628.3(ALOXE3):c.1889C>T(p.Pro630Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0018 ( 2 hom. )
Consequence
ALOXE3
NM_021628.3 missense
NM_021628.3 missense
Scores
13
2
2
Clinical Significance
Conservation
PhyloP100: 9.48
Genes affected
ALOXE3 (HGNC:13743): (arachidonate lipoxygenase 3) This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.829
PP5
?
Variant 17-8103390-G-A is Pathogenic according to our data. Variant chr17-8103390-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8103390-G-A is described in Lovd as [Pathogenic].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00182 (2658/1461864) while in subpopulation NFE AF= 0.00232 (2575/1111998). AF 95% confidence interval is 0.00224. There are 2 homozygotes in gnomad4_exome. There are 1282 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALOXE3 | NM_021628.3 | c.1889C>T | p.Pro630Leu | missense_variant | 15/16 | ENST00000448843.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALOXE3 | ENST00000448843.7 | c.1889C>T | p.Pro630Leu | missense_variant | 15/16 | 1 | NM_021628.3 | P1 | |
ALOXE3 | ENST00000380149.6 | c.1889C>T | p.Pro630Leu | missense_variant | 14/15 | 1 | P1 | ||
ALOXE3 | ENST00000318227.4 | c.1889C>T | p.Pro630Leu | missense_variant | 15/16 | 2 | P1 | ||
ALOXE3 | ENST00000583808.1 | n.126C>T | non_coding_transcript_exon_variant | 1/2 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00101 AC: 153AN: 152146Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00103 AC: 259AN: 251454Hom.: 0 AF XY: 0.000986 AC XY: 134AN XY: 135904
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GnomAD4 exome AF: 0.00182 AC: 2658AN: 1461864Hom.: 2 Cov.: 31 AF XY: 0.00176 AC XY: 1282AN XY: 727238
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2021 | One of the more common ALOXE3 variants, which is typically associated with a collodion membrane presentation at birth when homozygous; one patient compound heterozygous for P630L and a loss-of-function variant exhibited self-improving collodion ichthyosis (Vahlquist et al., 2010); Published functional studies demonstrate that P630L results in complete loss of eLOX-3 enzymatic activity (Eckl et al., 2005); This variant is associated with the following publications: (PMID: 31168818, 19890349, 31980526, 27025581, 16116617, 19131948, 30609409) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 630 of the ALOXE3 protein (p.Pro630Leu). This variant is present in population databases (rs147149459, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (ARCI) and ARCI or self-improving collodion ichthyosis (PMID: 16116617, 19131948, 19890349, 22622417, 27025581). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279677). 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 ALOXE3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ALOXE3 function (PMID: 16116617). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | ALOXE3: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting - |
Autosomal recessive congenital ichthyosis 3 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 20, 2018 | The ALOXE3 c.1889C>T (p.Pro630Leu) variant has been reported in four studies and is found in a total of 20 individuals with congenital ichthyosis including eight in a homozygous state and 12 in a compound heterozygous state (Eckl et al. 2005, Eckl et al. 2009, Vahlquist et al. 2010, Buckova et al. 2015). The p.Pro630Leu variant was absent from 290 controls and is reported at a frequency of 0.00157 in the European (non-Finnish) population of the Exome Aggregation Consortium. Eckl et al. (2005) demonstrated that HEK-293 cells expressing the p.Pro630Leu variant showed a complete loss of enzyme activity. Based on the collective evidence, the p.Pro630Leu variant is classified as pathogenic for autosomal recessive congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 22, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute for Human Genetics, University Medical Center Freiburg | Jan 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 27, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
ALOXE3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The ALOXE3 c.1889C>T variant is predicted to result in the amino acid substitution p.Pro630Leu. This variant has been reported in the homozygous or compound heterozygous state in individuals with congenital ichthyosis (see for example, Eckl et al. 2005. PubMed ID: 16116617; Table S1, Hellström Pigg et al. 2016. PubMed ID: 27025581; Table S2, Simpson et al. 2020. PubMed ID: 31168818; Appendix S4, Hake et al. 2022. PubMed ID: 34908195). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Lamellar ichthyosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2022 | Variant summary: ALOXE3 c.1889C>T (p.Pro630Leu) 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 0.001 in 251454 control chromosomes. The observed variant frequency is approximately 1.5 fold of our estimated maximal expected allele frequency for a pathogenic variant in ALOXE3 causing Lamellar Ichthyosis phenotype (0.00071). However, c.1889C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Autosomal Recessive, Ichthyosis (example, Eckl_2005, Li_2012, Pigg_2016, Diociaiuti_2016, Vahlquist_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of normal epidermal lipoxygenase activity (example, 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. - |
Autosomal recessive congenital ichthyosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 26, 2017 | The p.Pro762Leu variant in ALOXE3 (also referred to as NM_021628.2: p.Pro630Leu) has been reported in at least 6 homozygous and 10 compound heterozygous individ uals with autosomal recessive congenital icthyosis (Eckl 2005, Eckl 2009, Wang 2 015, Pigg 2016, and Diociaiuti 2016), and this variant also segregated in 4 indi viduals from 2 families (Eckl 2005). This variant has also been reported in Clin Var (Variation ID#279677). In vitro functional studies suggest the variant impac ts enzymatic function; however, these types of assays may not accurately represe nt biological function (Eckl 2005). This variant has been identified in 0.213% ( 270/126674) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs147149459). Although this variant has been seen in the general population, its frequency is low enough to be consisten t with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for congenital icthyosis in an autosomal recessive manner based upon segregation studies, functional evidence, and its biallelic oc currence in individuals with this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MVP
MPC
0.46
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at