rs190298665

chr18-23540528-A-Gchr18-23540528-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PM5 PP5

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). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F842S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 9.09

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 11 ACMG points.

• PS1: Transcript NM_000271.5 (NPC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1932106
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-23540527-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3007389.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 18-23540528-A-G is Pathogenic according to our data. Variant chr18-23540528-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499258.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2524T>C	p.Phe842Leu	missense_variant	17/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2524T>C	p.Phe842Leu	missense_variant	17/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1603T>C	p.Phe535Leu	missense_variant	10/18	2
NPC1	ENST00000540608.5	n.2438T>C		non_coding_transcript_exon_variant	15/16	2
NPC1	ENST00000586718.1	n.315T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152232 Hom.: 0 Cov.: 33

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: 9 AN: 251096 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135744

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: 18 AN: 1458036 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725630

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: 29 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74514

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.: 0

Bravo AF: 0.000616

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:1 Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 12, 2020	- -
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. -

NPC1-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

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 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	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.74		Loss of stability (P = 0.1532);
MVP		0.95
MPC		0.97
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs190298665; hg19: chr18-21120492;