rs372030650

Positions:

chr18-23539985-T-A

Variant summary

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

The NM_000271.5(NPC1):c.2621A>T(p.Asp874Val) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,934 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: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.10

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 topological_domain Lumenal (size 243) in uniprot entity NPC1_HUMAN there are 159 pathogenic changes around while only 14 benign (92%) in NM_000271.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 18-23539985-T-A is Pathogenic according to our data. Variant chr18-23539985-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23539985-T-A is described in Lovd as [Pathogenic]. Variant chr18-23539985-T-A is described in Lovd as [Pathogenic]. Variant chr18-23539985-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2621A>T	p.Asp874Val	missense_variant	18/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2621A>T	p.Asp874Val	missense_variant	18/25	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1700A>T	p.Asp567Val	missense_variant	11/18	2
NPC1	ENST00000540608.5 linkuse as main transcript	n.2535A>T		non_coding_transcript_exon_variant	16/16	2
NPC1	ENST00000586718.1 linkuse as main transcript	n.412A>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251354

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135872

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000187

AC:

274

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	The NPC1 c.2621A>T (p.Asp874Val) variant has been identified in seven studies in individuals with Niemann-Pick disease, including in a homozygous state in one proband, in a compound heterozygous state in 12 probands, in four additional proband alleles, and in one unaffected heterozygous individual (Sun et al. 2001; Bauer et al. 2002; Kaminski et al. 2002; Park et al. 2003; Bauer et al. 2013; Imrie et al. 2015; Davies-Thompson et al. 2016). The p.Asp874Val variant was absent from 341 controls and is reported at a frequency of 0.000111 in the European (non-Finnish) population of the Genome Aggregation Database. Dardis et al. (2016) demonstrated TAR DNA binding protein 43 localized to the cytoplasm in Purkinje cells versus localization in both cytoplasm and nucleus in Purkinje cells from a healthy individual. Based on the evidence, the p.Asp874Val variant is classified as pathogenic for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 874 of the NPC1 protein (p.Asp874Val). This variant is present in population databases (rs372030650, gnomAD 0.01%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 11333381, 11349231, 11754101, 12408188, 17160617, 23773996, 26666848). ClinVar contains an entry for this variant (Variation ID: 194810). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2022	Published functional studies found D874V is associated with impaired NPC1 protein localization (Shammas et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27544496, 23773996, 12408188, 11349231, 11333381, 23891399, 26666848, 30609409, 30690666, 31509197, 27193329, 12955717, 34113546, 30923329, 32204338) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -

Niemann-Pick disease, type C

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2016	The p.Asp874Val variant in NPC1 has been reported in at least 6 compound heteroz ygous and 1 homozygous individuals with classic Niemann-Pick disease C (Millat 2 001, Sun 2001, Kaminski 2002, Bauer 2013, Dardis 2016). This variant has also be en identified in 4/120,928 of chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs372030650). Although this variant h as been seen in the general population, its frequency is low enough to be consis tent with a recessive carrier frequency. In summary, the p.Asp874Val variant mee ts our criteria to be classified as pathogenic based on occurrence in trans with pathogenic variants in patients and low frequency in controls. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: NPC1 c.2621A>T (p.Asp874Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4.8e-05 vs 0.0027), allowing no conclusion about variant significance. c.2621A>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C. These data indicate that the variant may be associated with disease. Ten 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2021

The c.2621A>T (p.D874V) alteration is located in exon 18 (coding exon 18) of the NPC1 gene. This alteration results from an A to T substitution at nucleotide position 2621, causing the aspartic acid (D) at amino acid position 874 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the NPC1 c.2621A>T alteration was observed in 0.01% (15/282742) of total alleles studied. This mutation has been identified in the compound heterozygous state in several individuals with Niemann-Pick disease (Millat, 2001; Bauer, 2013; Imrie, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

NPC1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The NPC1 c.2621A>T variant is predicted to result in the amino acid substitution p.Asp874Val. This variant has been reported to be causative for Niemann-Pick disease (Millat et al. 2001. PubMed ID: 11333381; Bauer et al. 2013. PubMed ID: 23773996; Imrie et al. 2015. PubMed ID: 26666848). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.86

Sift

Uncertain

0.011

Sift4G

Benign

0.071

Polyphen

0.43

Vest4

0.75

MVP

0.96

MPC

0.38

ClinPred

0.79

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.81

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

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