chr18-23538609-C-G

Position:

chr18-23538609-C-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000271.5(NPC1):c.2974G>C(p.Gly992Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,186 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G992A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 6.09

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 Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000271.5 (NPC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a disulfide_bond (size 55) in uniprot entity NPC1_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 18-23538609-C-G is Pathogenic according to our data. Variant chr18-23538609-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23538609-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2974G>C	p.Gly992Arg	missense_variant	20/25	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.2974G>C	p.Gly992Arg	missense_variant	20/25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.2050G>C	p.Gly684Arg	missense_variant	13/18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000591075.1 linkuse as main transcript	n.607G>C		non_coding_transcript_exon_variant	2/3	4
NPC1	ENST00000591955.1 linkuse as main transcript	n.317G>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251484

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:6Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 23, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 14, 2004	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 992 of the NPC1 protein (p.Gly992Arg). This variant is present in population databases (rs80358254, gnomAD 0.02%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 11333381, 16126423, 26984608). ClinVar contains an entry for this variant (Variation ID: 2969). 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%. This variant disrupts the p.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9634529, 12955717, 16126423, 20718790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense variant c.2974G>Cp.Gly992Arg in NPC1 gene has been reported previously in individuals with Niemann-Pick disease type C. This variant is present in a mutational hotspot. Different amino acid changes p.Gly992Ala; p.Gly992Trp affecting the same position have been reported as pathogenic Sedel F, et al., 2016; Dardis A, et al., 2020. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Gly at position 992 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Niemann-Pick disease type C1 (MIM# 257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - This variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). Additionally, an alternative nucleotide change (G>A) resulting in the same amino acid substitution is also present in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a region within the cysteine-rich luminal loop where many missense variants have been reported (PMID: 16126423, PMID: 11333381). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two different variants in the same codon resulting in a changes to an alanine and a tryptophan have also been reported as pathogenic in patients with Niemann-Pick type C disease (ClinVar, PMID: 16126423, PMID: 32138288). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with Niemann-Pick type C disease. Additionally, another variant involving an alternative nucleotide change (G>A) that causes the same amino acid change has also been reported as pathogenic in patients with Niemann-Pick type C disease (ClinVar, PMID: 11333381, PMID: 32138288). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2019	PS1, PS4, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23821321, 23773996, 15596783, 16098014, 19307542, 28710748, 26984608, 25537619, 16126423, 24570279, 25349751, 20718790, 19609713, 19013089, 12205649, 11479732, 12955717, 26790753, 32138288, 34426522, 33360098, 31589614, 11333381, 34830064) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 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

Apr 26, 2017

Variant summary: The NPC1 c.2974G>C (p.Gly992Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121558 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). This variant has been reported in NPC patients (mostly adult-onset) both as homozygote and compound heterozygote. Another variant involving the same nucleotide G2974A, causing the same amino acid change G992R, has also been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.76

Sift

Benign

0.47

Sift4G

Benign

0.47

Polyphen

0.79

Vest4

0.92

MutPred

0.87

Gain of helix (P = 0.0325);

MVP

0.92

MPC

0.98

ClinPred

0.82

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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