rs147149459

chr17-8103390-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3 PP5_Very_Strong BS1_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• 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]

ACMG classification

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: 153 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00103 AC: 259 AN: 251454 Hom.: 0 AF XY: 0.000986 AC XY: 134 AN XY: 135904

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00182 AC: 2658 AN: 1461864 Hom.: 2 Cov.: 31 AF XY: 0.00176 AC XY: 1282 AN XY: 727238

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00232

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152264 Hom.: 0 Cov.: 31 AF XY: 0.000873 AC XY: 65 AN XY: 74466

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00218

EpiControl AF: 0.00166

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, 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	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, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Jan 07, 2021	- -
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	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2023	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.6	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MVP		0.99
MPC		0.46
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147149459; hg19: chr17-8006708;