Submissions for variant NM_000271.5(NPC1):c.1947+5G>C

gnomAD frequency: 0.00001  dbSNP: rs770321568

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000357223	SCV000333007	likely pathogenic	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000670237	SCV000795068	uncertain significance	Niemann-Pick disease, type C1	2017-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000670237	SCV002285585	pathogenic	Niemann-Pick disease, type C1	2023-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NPC1 protein in which other variant(s) (p.Gly640Arg) have been determined to be pathogenic (PMID: 12955717, 27581084). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 28328115). Studies have shown that this variant alters NPC1 gene expression (PMID: 30202070). ClinVar contains an entry for this variant (Variation ID: 281945). This variant has been observed in individual(s) with Niemann-Pick Type C (PMID: 28328115). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 12 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222467	SCV002500776	likely pathogenic	Niemann-Pick disease, type C	2022-03-30	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1947+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant affects mRNA splicing (Salman_2017). The variant allele was found at a frequency of 8e-06 in 249836 control chromosomes (gnomAD). c.1947+5G>C has been reported in the literature in individuals affected with Niemann-Pick Disease (e.g. Mazzacuva_2016, Salman_2017, Schultz_2018). These data indicate that the variant may be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003391029	SCV004119928	pathogenic	NPC1-related condition	2023-08-25	criteria provided, single submitter	clinical testing	The NPC1 c.1947+5G>C variant is predicted to interfere with splicing. This variant has been reported in individuals with Niemann-Pick disease, type C (Salman et al. 2017. PubMed ID: 28328115; Table S1, Mazzacuva et al. 2016. PubMed ID: 27139891). In vitro functional studies demonstrate this variant affects splicing as well as has an effect on NPC1 function (Figure 1C and D, Salman et al 2017. PubMed ID: 28328115; Figure 1D, Schultz et al. 2018. PubMed ID: 30202070 ). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21124919-C-G). This variant is interpreted as pathogenic.