Submissions for variant NM_000271.5(NPC1):c.1165C>T (p.Arg389Cys)

gnomAD frequency: 0.00001  dbSNP: rs1053321823

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001070899	SCV001236178	pathogenic	Niemann-Pick disease, type C1	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 389 of the NPC1 protein (p.Arg389Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with NPC1-related conditions (PMID: 12955717, 24178705, 33624863; Invitae). ClinVar contains an entry for this variant (Variation ID: 863837). 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.Arg389 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 19252935; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001070899	SCV002060059	uncertain significance	Niemann-Pick disease, type C1	2021-11-19	criteria provided, single submitter	clinical testing	NM_000271.4(NPC1):c.1165C>T(R389C) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease type C1. R389C has been observed in cases with relevant disease (PMID: 24178705, 33624863, 12955717). Functional assessments of this variant are not available in the literature. R389C has been observed in population frequency databases (gnomAD: AMR <0.003%). In summary, there is insufficient evidence to classify NM_000271.4(NPC1):c.1165C>T(R389C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV001070899	SCV003815165	likely pathogenic	Niemann-Pick disease, type C1	2022-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323794	SCV004030142	likely pathogenic	Niemann-Pick disease, type C	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1165C>T (p.Arg389Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251218 control chromosomes (gnomAD). c.1165C>T has been reported in the literature in the homozygous state in two individuals affected with Niemann-Pick Disease Type C, who exhibited cognitive impairment, ataxia and other motor symptoms, and in at least one other affected individual where it was reported as an uninformative genotype (i.e. zygosity not specified) (e.g. Park_2003, Anheim_2014, Vural_2021). These data indicate that the variant is likely to 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: 24178705, 12955717, 33624863). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001070899	SCV002095215	likely pathogenic	Niemann-Pick disease, type C1	2020-07-13	no assertion criteria provided	clinical testing