Submissions for variant NM_014363.6(SACS):c.2475dup (p.Val826fs)

dbSNP: rs1555252909

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479100	SCV000572391	likely pathogenic	not provided	2016-12-19	criteria provided, single submitter	clinical testing	The c.2475dupA variant in the SACS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2475dupA variant causes a frameshift starting with codon Valine 826, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Val826SerfsX6. This variant replaces the last 3754 amino acids with 5 incorrect residues and is predicted to cause loss of normal protein function through protein truncation. The lost region includes the HEPN domain, which is important for protein function. Additionally, protein truncating pathogenic variants downstream of this variant have been reported in the Human Gene Mutation Database in association with SACS-related disorders (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. The c.2475dupA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.2475dupA as a likely pathogenic variant.