ClinVar Genomic variation as it relates to human health

This variant was identified as homozygous.

The variant was co-segregated with UFSP2-related neurodevelopmental disorder and epilepsy in multiple affected family members (PMID: 33473208). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 33473208). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 33473208). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0001279). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces valine with glutamic acid at codon 115 of the UFSP2 protein (p.Val115Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs142500730, ExAC 0.1%). This missense change has been observed in individual(s) with UFSP2-related conditions (PMID: 33473208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932944). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

The observed missense variant c.344T>A (p.Val115Glu) in UFSP2 gene has been reported in homozygous state in multiple individuals affected with UFSP2-associated epilepsy syndrome. Experimental evidence has shown that homozygosity for this variant causes UFSP2 destabilization, reduced UFSP2 expression in fibroblasts (indicating a loss of function effect), and may lead to reduced protein stability and possibly reduced interaction with UFMylated targets (Ni et al. 2021). The p.Val115Glu variant is present with an allele frequency of 0.01% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Val115Glu in UFSP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 115 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

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 developmental and epileptic encephalopathy 106 (MIM#620028). The disease mechanism of spondyloepimetaphyseal dysplasia, Di Rocco type (MIM#617974) is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease. It is associated with autosomal recessive developmental and epileptic encephalopathy 106 (MIM#620028) and autosomal dominant spondyloepimetaphyseal dysplasia, Di Rocco type (MIM#617974). Its association with hip dysplasia, Beukes type (MIM#142669) is not well established (PanelApp Australia). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 32 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated UfSP2_N domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic/likely pathogenic by many clinical testing laboratories (ClinVar). It has also been reported as homozygous in individuals with early onset epilepsy (PMID: 33473208, DECIPHER). This variant has been reported as VUS by two clinical testing laboratories; however, no compelling evidence against pathogenicity was provided (ClinVar). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Fibroblast cell lines established from samples of affected individuals showed markedly reduced UFSP2 protein level (PMID: 33473208). The enhanced levels of several UFM1-conjugated proteins in those cell lines were normalised by the expression of wild-type UFSP2 (PMID: 33473208). The functional evidence is consistent with a loss of function disease mechanism. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The UFSP2 gene encodes a cysteine protease that participates in Ubiquitin-fold modifier 1 (UFM1) maturation in a process known as UFMylation and also releases UFM1 from UFMylated proteins in a process known as de-UFMylation. Both UFMylation and de-UFMylation are processes of post-translational protein modification, and functional studies have revealed that the loss of key components of these processes results in defects in embryogenesis, hematopoiesis, cellular differentiation, and brain development. Pathogenic variants (p.D426A, p.H428R, p.(Cys302Ser)) in two of the three components of the catalytic triad (Asp426 and His428) have already been associated with patients with different types of skeletal dysplasia. Homozygous variants (p.Val115Glu) were found to cause drug-refractory epilepsy and other brain defects. Specifically, p.Val115Glu was found to cause drug-refractory epilepsy and DD, whereas the Val115Glu variant was detected in patients with drug-refractory epilepsy, infantile spasms, and severe ID. In the current study, the p.Val115Glu variant was found to cause drug-refractory epilepsy, DD, ID, and anxiety in patients of a Pakistani family. Previous study findings suggested that variants observed in human skeletal dysplasia impact UFSP2's catalytic activity, whereas the homozygous p.Val115Glu variant found associated with brain defects impacts the N-terminal domain, including protein stability and interaction with UFMylated targets (PMID: 33473208).