rs190298665

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000271.5(NPC1):c.2524T>C(p.Phe842Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,610,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 9.09

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:

NPC1 (HGNC:):

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2524T>C	p.Phe842Leu	missense_variant	17/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2524T>C	p.Phe842Leu	missense_variant	17/25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1600T>C	p.Phe534Leu	missense_variant	10/18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 linkuse as main transcript	n.2438T>C		non_coding_transcript_exon_variant	15/16	2
NPC1	ENST00000586718.1 linkuse as main transcript	n.315T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251096

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

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:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1458036

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725630

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000190

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000295

Hom.:

Bravo

AF:

0.000616

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:1Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 842 of the NPC1 protein (p.Phe842Leu). This variant is present in population databases (rs190298665, gnomAD 0.02%). This missense change has been observed in individuals with Niemann-Pick Disease Type C (PMID: 29453517; Invitae). ClinVar contains an entry for this variant (Variation ID: 499258). 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.Phe842 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 02, 2021	The c.2524T>C, p.Phe842Leu missense variant identified in NPC1 has been reported in trans with a pathogenic variant in a 31-year-old patient with Niemann-Pick disease type C [PMID: 29453517]. This variant has twenty nine heterozygous alleles in the gnomAD v3 database consistent with the carrier frequency and in silico tools predict a deleterious effect. Based on the available evidence, the variant c.2524T>C, p.Phe842Leu in the NPC1gene is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 12, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

NPC1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

The NPC1 c.2524T>C variant is predicted to result in the amino acid substitution p.Phe842Leu. This variant has been reported in the compound heterozygous state in an individual with adult-onset Niemann-Pick disease type C (Zeiger et al. 2018. PubMed ID: 29453517) and was also identified in the analysis of a large sequencing dataset that did not include individuals with Niemann-Pick disease (Wassif et al. 2015. PubMed ID: 25764212). Additionally, this variant was seen in the compound heterozygous state in a patient at PreventionGenetics with biochemical findings that confirmed the diagnosis of Niemann-Pick disease. In summary, we interpret this variant as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 31, 2024

Variant summary: NPC1 c.2524T>C (p.Phe842Leu) 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 3.6e-05 in 251096 control chromosomes (gnomAD). c.2524T>C has been reported in the literature in individuals affected with Niemann-Pick disease, type C1 (Wassif_2015, Mazzacuva_2016, Zeiger_2018, Rodriguez-Gil_2021). These data indicate that the variant may 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: 27139891, 34296265, 25764212, 29453517). ClinVar contains an entry for this variant (Variation ID: 499258). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.65

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.84

MutPred

0.74

Loss of stability (P = 0.1532);

MVP

0.95

MPC

0.97

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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