NM_000271.5:c.3229C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000271.5(NPC1):​c.3229C>T​(p.Arg1077*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,686 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NPC1
NM_000271.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.13

Publications

5 publications found
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 Gene-Disease associations (from GenCC):
  • Niemann-Pick disease, type C1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
  • Niemann-Pick disease type C, adult neurologic onset
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Niemann-Pick disease type C, juvenile neurologic onset
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Niemann-Pick disease type C, late infantile neurologic onset
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Niemann-Pick disease type C, severe early infantile neurologic onset
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Niemann-Pick disease type C, severe perinatal form
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-23536689-G-A is Pathogenic according to our data. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23536689-G-A is described in CliVar as Pathogenic. Clinvar id is 289257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1NM_000271.5 linkc.3229C>T p.Arg1077* stop_gained Exon 21 of 25 ENST00000269228.10 NP_000262.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPC1ENST00000269228.10 linkc.3229C>T p.Arg1077* stop_gained Exon 21 of 25 1 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000591051.1 linkc.2305C>T p.Arg769* stop_gained Exon 14 of 18 2 ENSP00000467636.1 K7EQ23
NPC1ENST00000591075.1 linkn.*53C>T downstream_gene_variant 4
NPC1ENST00000591955.1 linkn.*11C>T downstream_gene_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251228
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461686
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727142
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.0000224
AC:
1
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86200
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111908
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:4
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2_Supporting+PVS1+PP4 -

Sep 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 289257). This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C (PMID: 27256227). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg1077*) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). -

Feb 03, 2025
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 28, 2017
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1
Jul 05, 2016
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.97
D
PhyloP100
2.1
Vest4
0.95
GERP RS
5.9
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs750095738; hg19: chr18-21116653; API