rs759826138

chr18-23539394-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000271.5(NPC1):c.2872C>T(p.Arg958Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,640 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R958R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NPC1 NM_000271.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.245

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 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 18-23539394-G-A is Pathogenic according to our data. Variant chr18-23539394-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 287837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23539394-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2872C>T	p.Arg958Ter	stop_gained	19/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2872C>T	p.Arg958Ter	stop_gained	19/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1951C>T	p.Arg651Ter	stop_gained	12/18	2
NPC1	ENST00000591075.1	n.505C>T		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251158 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135714

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 SAS 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: 0.00000342 AC: 5 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 07, 2023	This sequence change creates a premature translational stop signal (p.Arg958*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 287837). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11349231, 23773996). This variant is present in population databases (rs759826138, gnomAD 0.003%). -

Niemann-Pick disease, type C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 20, 2021

Variant summary: NPC1 c.2872C>T (p.Arg958X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251158 control chromosomes. c.2872C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (Sun_2001, Fancello_2009, Heron_2012, PerezMaturo_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication also reported experimental evidence evaluating an impact on protein function, and demonstrated impaired esterification of LDL-derived cholesterol in patient derived fibroblasts (Sun_2001). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 27, 2016

- -

Niemann-Pick disease, type C1, juvenile form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

May 23, 2019

This nonsense variant found in exon 19 of 25 is predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Niemann-Pick disease (PMID: 23773996). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00039% (1/251158) and thus is presumed to be rare. This variant has been previously classified as Pathogenic by multiple clinical labs in the ClinVar database (Variation ID: 287837). Based on the available evidence, the c.2872C>T (p.Arg958Ter) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	34
Dann	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.50	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		-4.8

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

LitVar

Other links and lift over

dbSNP: rs759826138; hg19: chr18-21119358;