NM_000271.5:c.3229C>T

Variant names:

• chr18-23536689-G-A
• rs750095738
• NM_000271.5:c.3229C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.13
• Publications: 5 publications found

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

ACMG classification

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
NPC1	NM_000271.5	c.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
NPC1	ENST00000269228.10	c.3229C>T	p.Arg1077*	stop_gained	Exon 21 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.2305C>T	p.Arg769*	stop_gained	Exon 14 of 18	2		ENSP00000467636.1
NPC1	ENST00000591075.1	n.*53C>T		downstream_gene_variant		4
NPC1	ENST00000591955.1	n.*11C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251228 AF XY: 0.00

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

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

dbSNP: rs750095738; hg19: chr18-21116653;