Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000270215 | SCV000407414 | uncertain significance | Autosomal recessive congenital ichthyosis 2 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002298570 | SCV002598697 | uncertain significance | not specified | 2023-12-14 | criteria provided, single submitter | clinical testing | Variant summary: ALOX12B c.526G>A (p.Glu176Lys) results in a conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00033 in 251140 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALOX12B causing Lamellar Ichthyosis (0.00033 vs 0.0009), allowing no conclusion about variant significance. c.526G>A has been reported in the literature in two homozygous individuals affected with congenital Ichthyosis (example: Hotz_2021), however one individual was also homozygous for a pathogenic variant in ALOXE3 (c.1193C>T/p.Ser398phe). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33435499, 35052464, 26863999). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV002523034 | SCV003267405 | uncertain significance | not provided | 2021-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 176 of the ALOX12B protein (p.Glu176Lys). This variant is present in population databases (rs149039053, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ALOX12B-related conditions. ClinVar contains an entry for this variant (Variation ID: 325890). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Institute for Human Genetics, |
RCV000270215 | SCV001477980 | pathogenic | Autosomal recessive congenital ichthyosis 2 | 2021-01-07 | no assertion criteria provided | clinical testing |