rs147149459

Positions:

chr17-8103390-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBS1_Supporting

The ENST00000448843.7(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
ENST00000448843.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.48

Variant links:

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]

ALOXE3 links:

Genome browser will be placed here

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	Protein	UniProt
ALOXE3	NM_021628.3 linkuse as main transcript	c.1889C>T	p.Pro630Leu	missense_variant	15/16	ENST00000448843.7	NP_067641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000448843.7 linkuse as main transcript	c.1889C>T	p.Pro630Leu	missense_variant	15/16	1	NM_021628.3	ENSP00000400581	P1	Q9BYJ1-1
ALOXE3	ENST00000380149.6 linkuse as main transcript	c.1889C>T	p.Pro630Leu	missense_variant	14/15	1		ENSP00000369494	P1	Q9BYJ1-1
ALOXE3	ENST00000318227.4 linkuse as main transcript	c.1889C>T	p.Pro630Leu	missense_variant	15/16	2		ENSP00000314879	P1	Q9BYJ1-1
ALOXE3	ENST00000583808.1 linkuse as main transcript	n.126C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152146

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000986

AC XY:

134

AN XY:

135904

show subpopulations

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.:

Cov.:

AF XY:

0.00176

AC XY:

1282

AN XY:

727238

show subpopulations

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.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74466

show subpopulations

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.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00218

EpiControl

AF:

0.00166

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
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 -
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	Labcorp Genetics (formerly Invitae), Labcorp	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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2023	- -
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	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 22, 2019	- -

ALOXE3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 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 multiple individuals with congenital ichthyosis (see for example, Eckl et al. 2005. PubMed ID: 16116617; Table S2, Hotz et al. 2021. PubMed ID: 33435499), self-improving collodion baby or congenital ichthyosis with fine/focal scaling (Table S1, Pigg et al. 2016. PubMed ID: 27025581), and non-bullous congenital ichthyosiform erythroderma (Table S2, Simpson et al. 2020. PubMed ID: 31168818). A functional study using HEK293 cells shows that this variant results in a loss of 12R-LOX and eLOX3 enzyme activity (Eckl et al. 2005. PubMed ID: 16116617). 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

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over