17-8103390-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3PP5BS1_Supporting
The NM_021628.3(ALOXE3):โc.1889C>Tโ(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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_021628.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ALOXE3 | ENST00000448843.7 | c.1889C>T | p.Pro630Leu | missense_variant | Exon 15 of 16 | 1 | NM_021628.3 | ENSP00000400581.2 | ||
| ALOXE3 | ENST00000380149.6 | c.1889C>T | p.Pro630Leu | missense_variant | Exon 14 of 15 | 1 | ENSP00000369494.2 | |||
| ALOXE3 | ENST00000318227.4 | c.1889C>T | p.Pro630Leu | missense_variant | Exon 15 of 16 | 2 | ENSP00000314879.4 | |||
| ALOXE3 | ENST00000583808.1 | n.126C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | 4 |
Frequencies
GnomAD3 genomes 0.00101 AC: 153AN: 152146Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00103 AC: 259AN: 251454Hom.: 0 AF XY: 0.000986 AC XY: 134AN XY: 135904
GnomAD4 exome AF: 0.00182 AC: 2658AN: 1461864Hom.: 2 Cov.: 31 AF XY: 0.00176 AC XY: 1282AN XY: 727238
GnomAD4 genome 0.00100 AC: 153AN: 152264Hom.: 0 Cov.: 31 AF XY: 0.000873 AC XY: 65AN XY: 74466
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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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) -
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ALOXE3: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -
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. -
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Autosomal recessive congenital ichthyosis 3 Pathogenic:6Uncertain:1
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 (Buฤkovรก 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. -
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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. -
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ALOXE3-related disorder Pathogenic:1
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at