Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001270889 | SCV001451669 | pathogenic | Netherton syndrome | 2019-02-20 | criteria provided, single submitter | clinical testing | The SPINK5 c.1111C>T (p.Arg371Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Arg371Ter variant has been reported in at least four studies, in which it is found in a total of seven individuals with Netherton syndrome, including in one in a homozygous state and six in a compound heterozygous state (Bitoun et al. 2002; Lacroix et al. 2012; Diociaiuti et al. 2013; Sitek et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000023 in the European (non-Finnish) population of the Genome Aggregation Database. Immunohistochemistry identified a complete absence of the SPINK5 protein in skin cells from the patient who carried the p.Arg371Ter variant in a homozygous state (Diociaiuti et al. 2013). Based on the collective evidence and application of the ACMG criteria, the p.Arg371Ter variant is classified as pathogenic for Netherton syndrome. |
| Invitae | RCV003595733 | SCV001577985 | pathogenic | Ichthyosis linearis circumflexa | 2022-03-23 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg371*) in the SPINK5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK5 are known to be pathogenic (PMID: 11511292, 11841556). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 989374). This premature translational stop signal has been observed in individual(s) with Netherton syndrome (PMID: 11841556). This variant is present in population databases (rs777436361, gnomAD 0.005%). |
| Victorian Clinical Genetics Services, |
RCV001270889 | SCV003921868 | pathogenic | Netherton syndrome | 2022-02-23 | criteria provided, single submitter | clinical testing | 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Netherton syndrome (MIM#256500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variation in disease severity has been reported in this gene (PMIDs: 11841556, 27905021). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as pathogenic/likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as homozygous or compound heterozygous in multiple individuals with Netherton syndrome (PMIDs: 11841556, 22089833, 23331056) and as pathogenic in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |