Submissions for variant NM_006432.5(NPC2):c.3G>C (p.Met1Ile)

dbSNP: rs483352893

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330496	SCV004038819	likely pathogenic	Niemann-Pick disease, type C	2023-08-22	criteria provided, single submitter	clinical testing	Variant summary: NPC2 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in frame initiation codon is at Met79. The variant was absent in 246888 control chromosomes. c.3G>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Zhang_2014). Additionally, disruptions of the start codon have been associated with pathogenicity in ClinVar and observed in multiple individuals with Niemann-Pick Diease (PMIDs: 19252935, 32138288). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24915861). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119339	SCV004297123	pathogenic	Niemann-Pick disease, type C2	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the NPC2 mRNA. The next in-frame methionine is located at codon 79. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Niemann-Pick disease type C (PMID: 19252935, 24915861). 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: 132902). This variant disrupts a region of the NPC2 protein in which other variant(s) (p.Cys47Phe) have been observed in individuals with NPC2-related conditions (PMID: 12955717, 15937921, 17470133). 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.
Shanghain Institute for Pediatric Research	RCV000119339	SCV000154198	pathogenic	Niemann-Pick disease, type C2		no assertion criteria provided	not provided	Converted during submission to Pathogenic.