rs80358259

chr18-23536736-A-G

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1061M) has been classified as Uncertain significance.

• 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:22 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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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	UniProt
NPC1	NM_000271.5	c.3182T>C	p.Ile1061Thr	missense_variant	21/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.3182T>C	p.Ile1061Thr	missense_variant	21/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.2261T>C	p.Ile754Thr	missense_variant	14/18	2
NPC1	ENST00000591955.1	n.525T>C		non_coding_transcript_exon_variant	2/2	4
NPC1	ENST00000591075.1			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:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:12 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, 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, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Mar 10, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
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, no assertion criteria provided	literature only	OMIM	Mar 28, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2016	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

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, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 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	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
MutationTaster	Benign	0.36	A;A
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;