ClinVar

Description

Variant summary: SEPSECS c.114+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. In addition, at least one minigene splicing assay revealed this variant results in skipping of exon 1 (Schlter_2022). However, one splicing assay reported cDNA sample from blood cells does not observe alteration in the splicing (Arrudi-Moreno_2021). The variant allele was found at a frequency of 4.6e-05 in 151924 control chromosomes (gnomAD). c.114+3A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Pontocerebellar Hypoplasia, Type 2D, inherited ataxia or genetic white matter disorders (Benkirane_2021, Arrudi-Moreno_2021, Schlter_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 32555262, 35155316, 35012964, 36085396, 31748115). Based on the evidence outlined above, the variant was classified as likely pathogenic.