Submissions for variant NM_021628.3(ALOXE3):c.1889C>T (p.Pro630Leu)

gnomAD frequency: 0.00105  dbSNP: rs147149459

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000295913	SCV000329062	pathogenic	not provided	2021-02-22	criteria provided, single submitter	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615069	SCV000713481	pathogenic	Autosomal recessive congenital ichthyosis	2017-09-26	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000032747	SCV000915793	pathogenic	Autosomal recessive congenital ichthyosis 3	2018-09-20	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV000295913	SCV001248911	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ALOXE3: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000032747	SCV001448962	pathogenic	Autosomal recessive congenital ichthyosis 3	2019-02-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000032747	SCV002025004	pathogenic	Autosomal recessive congenital ichthyosis 3	2023-02-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844106	SCV002103957	pathogenic	Lamellar ichthyosis	2022-02-21	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000295913	SCV003252132	pathogenic	not provided	2023-11-28	criteria provided, single submitter	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 (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.
PreventionGenetics, part of Exact Sciences	RCV003920029	SCV004731123	pathogenic	ALOXE3-related disorder	2024-02-09	criteria provided, single submitter	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 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000295913	SCV005199521	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000032747	SCV000056511	pathogenic	Autosomal recessive congenital ichthyosis 3	2009-06-01	no assertion criteria provided	literature only
Institute for Human Genetics, University Medical Center Freiburg	RCV000032747	SCV001477341	pathogenic	Autosomal recessive congenital ichthyosis 3	2021-01-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000295913	SCV001744249	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000295913	SCV001928589	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000295913	SCV001957344	pathogenic	not provided		no assertion criteria provided	clinical testing