ClinVar Genomic variation as it relates to human health

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.

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%).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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