Submissions for variant NM_000271.5(NPC1):c.3591+4del

gnomAD frequency: 0.00001  dbSNP: rs794727371

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176358	SCV000227999	uncertain significance	not provided	2014-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386022	SCV001586103	pathogenic	Niemann-Pick disease, type C1	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change falls in intron 23 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs794727371, gnomAD 0.002%). This variant has been observed in individual(s) with Niemann-Pick Type C (PMID: 26666848, 28710748). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195722). 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. For these reasons, this variant has been classified as Pathogenic.