ClinVar

Description

This sequence change affects a donor splice site in intron 21 of the EVC2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs200300612, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Ellis-van Creveld syndrome (PMID: 17024374, 23220543; Invitae). ClinVar contains an entry for this variant (Variation ID: 348980). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the EVC2 protein in which other variant(s) (p.Ser1220Argfs*3) have been determined to be pathogenic (PMID: 12571802, 17024374, 19810119, 23220543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.