Submissions for variant NM_000271.5(NPC1):c.1547G>A (p.Cys516Tyr) (rs751951695)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000258907	SCV000328674	likely pathogenic	not provided	2016-11-07	criteria provided, single submitter	clinical testing	The C516Y variant in the NPC1 gene has been observed in internal GeneDx whole exome sequencing data in association with hydrops, pancytopenia, acute liver failure, seizures, ataxia, and cognitive dysfunction. This 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. The C516Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (H510P, H512R, R518W, R518Q, and A521S) have been reported in the Human Gene Mutation Database in association with Niemann-Pick disease type C (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret C516Y as a likely pathogenic variant.