rs80358259

Positions:

chr18-23536736-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000271.5(NPC1):c.3182T>C(p.Ile1061Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Lumenal (size 243) in uniprot entity NPC1_HUMAN there are 84 pathogenic changes around while only 9 benign (90%) in NM_000271.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 18-23536736-A-G is Pathogenic according to our data. Variant chr18-23536736-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536736-A-G is described in Lovd as [Pathogenic]. Variant chr18-23536736-A-G is described in Lovd as [Pathogenic]. Variant chr18-23536736-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.3182T>C	p.Ile1061Thr	missense_variant	21/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.3182T>C	p.Ile1061Thr	missense_variant	21/25	1	NM_000271.5	ENSP00000269228	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.2261T>C	p.Ile754Thr	missense_variant	14/18	2		ENSP00000467636
NPC1	ENST00000591955.1 linkuse as main transcript	n.525T>C		non_coding_transcript_exon_variant	2/2	4
NPC1	ENST00000591075.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251430

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000513

AC:

750

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000480

AC XY:

349

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000644

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000223

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000923

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:13Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Mar 10, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	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. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 07, 2015	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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). 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%. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 28, 2008	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NPC1: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -

Niemann-Pick disease, type C

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2022

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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

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. -

NPC1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.36

A;A

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.88

Vest4

0.87

MVP

0.96

MPC

0.49

ClinPred

0.27

GERP RS

6.0

Varity_R

0.60

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over