rs781065429

Positions:

chr18-23554960-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000271.5(NPC1):c.1351G>A(p.Glu451Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,612,928 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 5.87

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:

NPC1 (HGNC:):

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Lumenal (size 248) in uniprot entity NPC1_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000271.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 18-23554960-C-T is Pathogenic according to our data. Variant chr18-23554960-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554990.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.1351G>A	p.Glu451Lys	missense_variant	9/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.1351G>A	p.Glu451Lys	missense_variant	9/25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.631G>A	p.Glu211Lys	missense_variant	4/18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 linkuse as main transcript	n.1265G>A		non_coding_transcript_exon_variant	7/16	2
NPC1	ENST00000590301.1 linkuse as main transcript	n.26G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251370

Hom.:

AF XY:

0.0000589

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1460790

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726802

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:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 451 of the NPC1 protein (p.Glu451Lys). This variant is present in population databases (rs781065429, gnomAD 0.03%). This missense change has been observed in individual(s) with Niemann-Pick, Type C (PMID: 26790753). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554990). 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 not expected to disrupt NPC1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 11, 2017	The NPC1 c.1351G>A (p.Glu451Lys) variant has been reported in a compound heterozygous state with the same second missense variant in seven individuals from two families, a pair of siblings in one family and five siblings in the second family (Tarugi et al. 2002; Romanello et al. 2016). While all individuals were noted to have Niemann-Pick disease (NPCD), four siblings were 'not classified' due to absence of neurological symptoms (Romanello et al. 2016). In addition, the five siblings exhibited a variant biochemical phenotype based on filipin staining and specific types of oxysterols were observed at either below or slightly above the cut-off noted in patients with NPCD (Romanello et al. 2016). The p.Glu451Lys variant was also identified in a heterozygous state in one individual with the early infantile form who also displayed the variant biochemical phenotype; however, in this individual, a second variant was not identified (De Castro-Oros et al. 2017). The p.Glu451Lys variant was absent from 300 control alleles and is reported at a frequency of 0.000305 in the South Asian population of the Exome Aggregation Consortium. Functional studies of the variant have not been conducted, but it results in a nonconservative substitution of a highly conserved amino acid (Tarugi et al. 2002). Based on the collective evidence, the p.Glu451Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 10, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	NPC1: PM3:Very Strong, PM2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2017	- -

Niemann-Pick disease, type C

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 30, 2024

Variant summary: NPC1 c.1351G>A (p.Glu451Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251370 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4e-05 vs 0.0027), allowing no conclusion about variant significance. c.1351G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Tarugi_2002, Benussi_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12401890, 28222799, 26790753, 31497485, 26771826). ClinVar contains an entry for this variant (Variation ID: 554990). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.079

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.57

Sift

Benign

0.80

Sift4G

Benign

0.91

Polyphen

0.055

Vest4

0.81

MutPred

0.81

Gain of ubiquitination at E451 (P = 0.0185);

MVP

0.86

MPC

0.30

ClinPred

0.12

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.31

gMVP

0.86

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