rs2064355122

Description

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).

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.