Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000967782 | SCV001115201 | likely benign | not provided | 2019-12-31 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265752 | SCV002548456 | uncertain significance | not specified | 2022-05-24 | criteria provided, single submitter | clinical testing | Variant summary: CASP14 c.462_463delCA (p.Asp154GlufsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00043 in 150844 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0035 in the gnomAD database (v3.1 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASP14 causing (severe) Lamellar Ichthyosis phenotype (0.00025), suggesting that the variant is likely not associated with a severe, highly penetrant ichthyotic phenotype. On the other hand, the variant, c.462_463delCA, has also been reported in the literature in three homozygous individuals, from two families, who were affected with a mild form of ichthyosis, although phenotype details were provided only for one of these patients, describing whitish scales over body, without erythema or other symptoms (Kirchmeier_2017). These data indicate that the variant might be associated with a milder disease, possibly with incomplete penetrance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other truncations have been reported in affected individuals (HGMD). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for a milder disease phenotype. |
| OMIM | RCV000416366 | SCV000494078 | pathogenic | Ichthyosis, congenital, autosomal recessive 12 | 2017-01-27 | no assertion criteria provided | literature only |