ClinVar Genomic variation as it relates to human health

This nonsense variant found in exon 8 of 8 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 10 amino acids of the SNAP25 protein. This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. This result was confirmed by Sanger sequencing. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.589C>T (p.Gln197Ter) variant is classified as Likely Pathogenic.

This variant was identified as de novo (maternity and paternity confirmed).

The variant c.589C>T (p.Gln197*) in the SNAP25 gene is reported as likely pathogenic for myasthenic syndrome, congenital, 18 in ClinVar (Variation ID: 986340). It creates a premature stop codon at amino acid position Gln197 which is likely to result in the alteration of the C-terminal end of the SNAP25 protein. There is no information on frequency in gnomAD or 1000 Genomes Project. In a very recent article, it is reported that de novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy. The authors reported 19 individuals harboring heterozygous de novo missense or loss-of-function variants in SNAP25, determined to be pathogenic or likely pathogenic. Particularly, the authors reported a 11 months child harboring the heterozygous mutation c.589C>T (p.Gln197*) (Klöckner et al., 2021, PMID: 33299146). Alten and colleagues (2021) reported the case of two affected siblings, who inherited a pathogenic variant in the SNAP25 gene from the unaffected mosaic father (PMID: 33147442).

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 4-Likely pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene. Only 1 missense variant has been proven to exert a dominant-negative effect (PMID: 25381298). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. This variant results in the loss of the last nine amino acids. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 – The amino acids affected by the truncation are highly conserved. (SP) 0600 - Variant is located in the annotated t-SNARE coiled-coil homology 2 domain (PDB) (I) 0705 - No comparable truncating variants have previous evidence for pathogenicity. No published evidence of truncating variants downstream. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated the truncated protein (aa 1-197) resulted in reduced binding to G-beta-gamma and therefore reduction in vesicle fusion events (PMID: 15834421, 15044754). (SP) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 10 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 36007526, 30724471, 33299146)

The SNAP25 c.589C>T variant is predicted to result in premature protein termination (p.Gln197*). This variant was reported as de novo in an individual with developmental encephalopathy (Klöckner et al. 2020. PubMed ID: 33299146). This variant was also reported in an additional individual with clinical features consistent with a SNAP25-related disorder and was reported to occur de novo (Subject ID 147, Table S8 and S9 in Kingsmore SF et al 2022. PubMed ID: 36007526; Rady Children's https://www.ncbi.nlm.nih.gov/clinvar/variation/986340/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is reported in ClinVar as likely pathogenic by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/986340/). This variant is interpreted as likely pathogenic.