chr17-8103390-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PP3PP5_Very_StrongBS1_SupportingBS2_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.48

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALOXE3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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 VariationId is 279677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 1282 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOXE3	NM_021628.3 link	c.1889C>T	p.Pro630Leu	missense_variant	Exon 15 of 16	ENST00000448843.7	NP_067641.2	Q9BYJ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000448843.7 link	c.1889C>T	p.Pro630Leu	missense_variant	Exon 15 of 16	1	NM_021628.3	ENSP00000400581.2		Q9BYJ1-1

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

GnomAD2 exomes

AF:

0.00103

AC:

259

AN:

251454

AF XY:

0.000986

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00232

AC:

2575

AN:

1111998

Other (OTH)

AF:

0.000911

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

151

303

454

606

757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

153

AN:

152264

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41540

American (AMR)

AF:

0.000327

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00193

AC:

131

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00144

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:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3

Pathogenic:7

Jun 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2021

Institute for Human Genetics, University Medical Center Freiburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 27, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 21, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ALOXE3 c.1889C>T (p.Pro630Leu) variant has been reported in at least 20 individuals affected with autosomal recessive congenital ichthyosis. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (Bučková H et al., PMID: 25998749; Eckl KM et al., PMID: 16116617; Eckl KM et al. PMID: 19131948; Pigg MH et al., PMID: 27025581; Vahlquist A et al., PMID: 19890349). This variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar ID: 279677). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.2% in the European non-Finnish population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to ALOXE3 function. Functional studies show that p.Pro630Leu results in complete loss of eLOX-3 enzymatic activity in HEK293 cells indicating that this variant impacts protein function (Eckl KM et al., PMID: 16116617). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

not provided

Pathogenic:7

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALOXE3: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive congenital ichthyosis

Pathogenic:2

Sep 26, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 26, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALOXE3-related disorder

Pathogenic:1

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

(source)

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;.

PhyloP100

9.5

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

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over