Submissions for variant NM_000271.5(NPC1):c.2366G>A (p.Arg789His)

dbSNP: rs483352891

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000119335	SCV001369459	likely pathogenic	Niemann-Pick disease, type C1	2019-10-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP3,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119335	SCV002290225	pathogenic	Niemann-Pick disease, type C1	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 789 of the NPC1 protein (p.Arg789His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 24915861, 29429782). 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: 132898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg789 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 11349231), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230407	SCV003928904	uncertain significance	not specified	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.2366G>A (p.Arg789His) results in a non-conservative amino acid change located in the Sterol-sensing domain (IPR000731) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251460 control chromosomes (gnomAD). c.2366G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (example: Berry Kravis_2018 and Zhang_2014). Other variants affecting the same amino acid residue is associated with Niemann-Pick disease, type C and is classified pathogenic/likely pathogenic in ClinVar (CV ID: 1326279, 554973). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29429782, 24915861). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Shanghain Institute for Pediatric Research	RCV000119335	SCV000154194	pathogenic	Niemann-Pick disease, type C1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.