Submissions for variant NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)

gnomAD frequency: 0.00025  dbSNP: rs80358259

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254672	SCV000208911	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	In vitro studies of I1061T in human fibroblasts demonstrated that the protein fails to undergo normal glycosylation, leading to misfolding and degradation (Gelsthorpe et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28865947, 31589614, 31980526, 32138288, 31639011, 29476731, 29631617, 28776642, 28413817, 27923633, 25873482, 10480349, 25637190, 26019327, 24928400, 25149939, 10521297, 22505584, 23430855, 21436030, 20521171, 18216017, 25590979, 23521787, 26666848, 14639697, 28710748, 30487145, 30665703, 30556376)
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000003101	SCV000236543	pathogenic	Niemann-Pick disease, type C1	2015-03-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000254672	SCV000330979	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000003101	SCV000596044	pathogenic	Niemann-Pick disease, type C1	2016-11-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003101	SCV000611222	pathogenic	Niemann-Pick disease, type C1	2022-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587869	SCV000696420	pathogenic	Niemann-Pick disease, type C	2022-06-28	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3182T>C (p.Ile1061Thr) 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 0.0002 in 251630 control chromosomes. This variant has been shown to be the most common mutation in NPC patients (Millat_1999). Functional study showed that the protein levels of NPC1 I1061T was significantly lower than the wild-type NPC1 due to misfolding (Gelsthorpe_2008). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000624446	SCV000742470	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003101	SCV000836750	pathogenic	Niemann-Pick disease, type C1	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1061 of the NPC1 protein (p.Ile1061Thr). This variant is present in population databases (rs80358259, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 20521171, 25149939). It is commonly reported in individuals of American and Western European ancestry (PMID: 10521297). ClinVar contains an entry for this variant (Variation ID: 2967). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NPC1 function (PMID: 18216017, 25637190, 26019327). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000003101	SCV001163434	pathogenic	Niemann-Pick disease, type C1		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000003101	SCV001193866	pathogenic	Niemann-Pick disease, type C1	2019-11-12	criteria provided, single submitter	clinical testing	NM_000271.4(NPC1):c.3182T>C(I1061T) is classified as pathogenic in the context of Niemann-Pick disease, type C1. Sources cited for classification include the following: PMID 12401890, 10521290, 10480349, 21436030, 16098014, 11349231, 11754101, 18216017 and 22505584. Classification of NM_000271.4(NPC1):c.3182T>C(I1061T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000254672	SCV001249522	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	NPC1: PM3:Very Strong, PM2, PS3:Supporting
Revvity Omics, Revvity	RCV000003101	SCV002018348	pathogenic	Niemann-Pick disease, type C1	2022-01-11	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000254672	SCV002502267	pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000003101	SCV003919012	pathogenic	Niemann-Pick disease, type C1	2023-04-20	criteria provided, single submitter	research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335012	SCV004046002	pathogenic	Sphingomyelin/cholesterol lipidosis		criteria provided, single submitter	clinical testing	This variant is one of the most common alterations identified in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 25149939, 20521171, 10480349). Functional characterization showed that the variant impairs proper protein localization and leads to proteasomal degradation in cell culture (PMID: 18216017, 25637190). The c.3182T>C (p.Ile1061Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.019% (53/282832) and thus is presumed to be rare. The c.3182T>C (p.Ile1061Thr) variant is predicted by in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3182T>C (p.Ile1061Thr) variant is classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003101	SCV005086756	pathogenic	Niemann-Pick disease, type C1	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type C1 Niemann-Pick disease (MIM#257220) and type D Niemann-Pick disease (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been observed amongst individuals carrying the same pathogenic variant (PMID: 32138288). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (53 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid c(SP) 0600 - Variant is located in the annotated Patched family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous or homozygous in many individuals with Niemann-Pick disease type C1 (PMID: 35140266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003101	SCV000023259	pathogenic	Niemann-Pick disease, type C1	2008-03-28	no assertion criteria provided	literature only
GeneReviews	RCV000003101	SCV000040577	not provided	Niemann-Pick disease, type C1		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000003101	SCV000238437	pathogenic	Niemann-Pick disease, type C1	2015-05-07	no assertion criteria provided	research	The heterozygous variant in the NPC1 gene (c.3182T>C; p.Ile1061Thr) is considered pathogenic. This variant was seen in 29 alleles out of 120942 total interrogated at this position in the ExAC database. This variant has been previously published in multiple individuals (Fernandez-Valero et al. 2005; PMID: 16098014; MIlat et al. 1999 PMID: 10521297; Yamamoto et al. 1999, PMID: 10480349) and functional studies performed show that the resulting protein fails to localize properly (Gelsthorpe et al 2008, PMID: 18216017).
Natera, Inc.	RCV000003101	SCV001453832	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000254672	SCV001743369	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000003101	SCV001760424	pathogenic	Niemann-Pick disease, type C1		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000254672	SCV001971474	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964790	SCV004785140	pathogenic	NPC1-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The NPC1 c.3182T>C variant is predicted to result in the amino acid substitution p.Ile1061Thr. This variant has been repeatedly documented as causative for Niemann-Pick disease (Yamamoto et al. 1999. PubMed ID: 10480349; Gelsthorpe et al. 2008. PubMed ID: 18216017). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.