Submissions for variant NM_000271.5(NPC1):c.3410dup (p.Asn1137fs) (rs768299417)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000825536	SCV000966852	likely pathogenic	Niemann-Pick disease, type C	2017-06-28	criteria provided, single submitter	clinical testing	The p.Asn1137LysfsX121 (NM_000271.4 c.3410_3411insA) variant in NPC1 has not be en previously reported in the literature. This variant has been identified in 1/ 111564 of European chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomAD.broadinstitute.org; dbSNP rs768299417). It is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 113 7 and leads to a premature termination codon 121 amino acids downstream. This al teration is then predicted to lead to a truncated or absent protein. Biallelic l oss of function of the NPC1 gene is associated with Niemann-Pick disease, type C 1. In summary, although additional studies are required to fully establish a nul l effect on the protein, the p.Asn1137LysfsX121 variant in the NPC1 gene is lik ely pathogenic for Niemann-Pick disease, type C1 in an autosomal recessive manne r based on its predicted impact on the protein.