NM_000271.5:c.2932C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000271.5(NPC1):c.2932C>T(p.Arg978Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,700 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.52

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 16 ACMG points.

PM1

In a disulfide_bond (size 55) in uniprot entity NPC1_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_000271.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 18-23538651-G-A is Pathogenic according to our data. Variant chr18-23538651-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23538651-G-A is described in Lovd as [Pathogenic]. Variant chr18-23538651-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.2932C>T	p.Arg978Cys	missense_variant	Exon 20 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.2932C>T	p.Arg978Cys	missense_variant	Exon 20 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.2008C>T	p.Arg670Cys	missense_variant	Exon 13 of 18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000591075.1 link	n.565C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4
NPC1	ENST00000591955.1 link	n.275C>T		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251346

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000828

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:4

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant in a 15-year-old female with Niemann-Pick Type C -

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 978 of the NPC1 protein (p.Arg978Cys). This variant is present in population databases (rs28942108, gnomAD 0.01%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (NPC) (PMID: 11349231, 11479732, 15459971, 20718790, 22750297, 23427322, 23433426, 23774949, 26984608; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2976). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Oct 21, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals heterozygous for R978C and another pathogenic variant in NPC1 in association with variant Niemann-Pick disease type C biochemical phenotype and highly variable symptoms and age of onset, ranging from neonatal liver disease to gait ataxia and dysarthria at the age of 20 (Sun et al., 2001; Macias-Vidal et al., 2011; Di Leo et al., 2004; Abela et al., 2014; Perez-Poyato et al., 2012); This variant is associated with the following publications: (PMID: 22750297, 11349231, 15459971, 11479732, 26984608, 24035292, 20718790, 23433426, 28332184, 25425405, 31639011, 32138288, 31589614) -

Dec 01, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type C

Pathogenic:1

Nov 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg978Cys variant in NPC1 has been reported in 1 heterozygous individual with Parkinson disease and 9 individuals with the variant form and/or juvenile/adult onset of Niemann-Pick disease type C (Di Leo 2004, Kluenemann 2013, Macia-Vidal 2011, Perez-Poyato 2012, Riberio 2001, Schicks 2013, Sedel 2016, Stampfer 2013, Sun 2001). All of the 9 individuals also carried another variant in NPC1 in trans, with at least 2 being known disease-causing variants. It also segregated along with another variant in NPC1 in trans in 4 affected relatives from 3 families (Di Leo 2004, Kluenemann 2013). This variant has also been reported in ClinVar (Variation ID 2976). p.Arg978Cys variant has been identified in 1/9848 of Ashkenazi Jewish and 2/111684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs28942108). Although this variant has been seen in the general population, its frequency is low enough to be consistent with carrier frequency for Niemann-Pick disease type C. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for the variant form of Niemann-Pick disease type C in an autosomal recessive manner. ACMG/AMP Criteria applied: PM2; PM3_VeryStrong; PP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.81

Sift

Benign

0.050

Sift4G

Uncertain

0.052

Polyphen

0.95

Vest4

0.68

MutPred

0.85

Loss of loop (P = 0.0374);

MVP

0.98

MPC

0.63

ClinPred

0.83

GERP RS

5.2

Varity_R

0.12

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -8

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