rs80358259

Variant names:

• chr18-23536736-A-G
• rs80358259
• NM_000271.5:c.3182T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

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 rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.3182T>C	p.Ile1061Thr	missense_variant	Exon 21 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.3182T>C	p.Ile1061Thr	missense_variant	Exon 21 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.2258T>C	p.Ile753Thr	missense_variant	Exon 14 of 18	2		ENSP00000467636.1
NPC1	ENST00000591955.1	n.525T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
NPC1	ENST00000591075.1	n.*6T>C		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152228 Hom.: 0 Cov.: 32

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: 51 AN: 251430 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135906

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.: 0 Cov.: 32 AF XY: 0.000480 AC XY: 349 AN XY: 727242

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: 34 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74378

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.: 1

Bravo AF: 0.000227

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:13 Other:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 10, 2015

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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). -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 18, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6

Feb 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Mar 17, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC1: PM3:Very Strong, PM2, PS3:Supporting -

Niemann-Pick disease, type C Pathogenic:1

Jun 28, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sphingomyelin/cholesterol lipidosis Pathogenic:1

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

NPC1-related disorder Pathogenic:1

Jul 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.88	P
Vest4		0.87
MVP		0.96
MPC		0.49
ClinPred		0.27	T
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

Other links and lift over

dbSNP: rs80358259; hg19: chr18-21116700; COSMIC: COSV52571926; COSMIC: COSV52571926;