rs377515417

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000271.5(NPC1):c.1552C>T(p.Arg518Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,458,344 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense, splice_region

Scores

Splicing: ADA: 0.02604

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.65

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 14 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-23554758-C-T is described in Lovd as [Likely_pathogenic].

PP5

Variant 18-23554759-G-A is Pathogenic according to our data. Variant chr18-23554759-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23554759-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1552C>T	p.Arg518Trp	missense_variant, splice_region_variant	9/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1552C>T	p.Arg518Trp	missense_variant, splice_region_variant	9/25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.832C>T	p.Arg278Trp	missense_variant, splice_region_variant	4/18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1466C>T		splice_region_variant, non_coding_transcript_exon_variant	7/16	2
NPC1	ENST00000590301.1 link	n.227C>T		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251038

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135672

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:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1458344

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725732

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000464

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 09, 2020	- -
Likely 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	Sep 08, 2023	For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 550874). This variant is present in population databases (rs377515417, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 22676771, 26666848, 27366019, 28222799). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 518 of the NPC1 protein (p.Arg518Trp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 02, 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

Mar 18, 2022

Variant summary: NPC1 c.1552C>T (p.Arg518Trp) results in a non-conservative amino acid change located in the luminal loop between TM 2 and 3 (Ribeiro_2001) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251150 control chromosomes (gnomAD and publication data). c.1552C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (Ribeiro_2001, Imrie_2006, Lee_2016, Bowman_2017, Perez Maturo_2020). In addition, this variant was found in three homozygous patients (siblings) in one family (Imrie_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Missense variants in nearby residues (H512R, C156Y, A521S, H530Y) have been reported in the Human Gene Mutation Database in association with Niemann-Pick Disease Type C, supporting the functional importance of this region of the protein. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). 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

0.24

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.76

Sift

Uncertain

0.010

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.50

MVP

0.93

MPC

0.80

ClinPred

0.82

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.026

dbscSNV1_RF

Benign

0.23

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