rs80358257

Positions:

• chr18-23538564-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000271.5(NPC1):​c.3019C>G​(p.Pro1007Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,614,108 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 U:1 O:1
• Conservation: PhyloP100: 9.91

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 14 ACMG points.

• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 18-23538564-G-C is Pathogenic according to our data. Variant chr18-23538564-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23538564-G-C is described in Lovd as [Pathogenic]. Variant chr18-23538564-G-C is described in Lovd as [Likely_pathogenic]. Variant chr18-23538564-G-C is described in Lovd as [Pathogenic]. Variant chr18-23538564-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.3019C>G	p.Pro1007Ala	missense_variant	20/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.3019C>G	p.Pro1007Ala	missense_variant	20/25	1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.2098C>G	p.Pro700Ala	missense_variant	13/18	2		ENSP00000467636
NPC1	ENST00000591075.1	n.652C>G		non_coding_transcript_exon_variant	2/3	4
NPC1	ENST00000591955.1	n.362C>G		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251490 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 128 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74428

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:16 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 03, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1007 of the NPC1 protein (p.Pro1007Ala). This variant is present in population databases (rs80358257, gnomAD 0.02%). This missense change has been observed in individual(s) with Niemann-Pick type C disease (PMID: 10521290, 11754101, 14639697, 23183285, 23791518, 25425405, 26981555). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2966). 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%. Experimental studies have shown that this missense change does not substantially affect NPC1 function (PMID: 15937921). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 24, 2023	Identified as compund heterozygous with NM_000271.5:c.1997G>A. Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 09, 2022	ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP1 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing for Niemann-Pick disease, type C [PMID 14639697, 23773996, 23791518, 23427322, 26666848] -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000271.4(NPC1):c.3019C>G(P1007A) is classified as pathogenic in the context of Niemann-Pick disease type C1. Sources cited for classification include the following: PMID 16098014, 11479732 and 11333381. Classification of NM_000271.4(NPC1):c.3019C>G(P1007A) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The NPC1 gene is one of two genes in which variants are known to cause Niemann-Pick disease type C. The NPC1 c.3019C>G (p.Pro1007Ala) variant is widely reported as a pathogenic variant and is the second most common pathogenic allele in Western Europe and the US (Patterson et al. 2000). Across a selection of the available literature, the p.Pro1007Ala variant has been identified in at least 44 Niemann-Pick disease type C patients including eight in a homozygous state, 33 in a compound heterozygous state, and three in a heterozygous state (Greer et al. 1999; Ribeiro et al. 2001; Sun et al. 2001; Millat et al. 2001; Bauer et al. 2002; Tarugi et al. 2002; Fernandez-Valero et al. 2005; Jahnova et al. 2014; Pina-Aguilar et al. 2014; Abela et al. 2014; Imrie et al. 2015). The p.Pro1007Ala variant is described as being associated with a variant form of Niemann-Pick disease type C, which presents with a non-classical biochemical profile (Millat et al. 2001; Sun et al. 2001). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence the p.Pro1007Ala 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 07, 2021	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 12955717; 20554533) - PS3_moderate.The c.3019C>G;p.(Pro1007Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2966; PMID 14639697; PMID: 23773996; PMID: 23791518; PMID: 23427322; PMID: 26666848) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain PM1. The variant is present at low allele frequencies population databases (rs80358257 – gnomAD 0.001167%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Pro1007Ala) was detected in trans with a pathogenic variant (PMID 14639697; PMID: 23773996; PMID: 23791518) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	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: 24676439, 28332184, 32222928, 31980526, 23487299, 24570279, 25131710, 23183285, 28105569, 26981555, 23427322, 26790753, 10521290, 26338816, 24119781, 25236789, 30202070, 28186668, 24915861, 23773996, 23791518, 24386122, 14639697, 11349231, 26666848, 30548255, 16126423, 32138288, 32488064, 33726816) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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.3019C>G (p.Pro1007Ala) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 14/121408 control chromosomes at a frequency of 0.0001153, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant has been reported numerous times in the literature in affected individuals in both the homozygous and compound heterozygous state. Multiple clinical labs classify the variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2021

The c.3019C>G (p.P1007A) alteration is located in exon 20 (coding exon 20) of the NPC1 gene. This alteration results from a C to G substitution at nucleotide position 3019, causing the proline (P) at amino acid position 1007 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD) database, the NPC1 c.3019C>G alteration was observed in 0.01% (33/282878) of total alleles studied, with a frequency of 0.02% (29/129196) in the European (non-Finnish) subpopulation. This mutation has been identified in numerous homozygous and compound heterozygous individuals with NPC1-related Niemann-Pick disease, many with intermediate or "variant" levels of cholesterol esterification (Millat, 2001; Jahnova, 2014; Reunert, 2016; Musalkova, 2020; Dardis, 2020). The p.P1007A 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

Sep 25, 2024

The NPC1 c.3019C>G variant is predicted to result in the amino acid substitution p.Pro1007Ala. This variant has been well-documented as causative for Niemann-Pick disease (see for example Greer et al. 1999. PubMed ID: 10521290; Bauer et al. 2013. PubMed ID: 23773996; Mavridou et al. 2017. PubMed ID: 28105569; Dardis et al. 2020. PubMed ID: 32138288). Other missense variants, affecting the same amino acid (p.Pro1007Leu, p.Pro1007Arg), have also been reported to be causative for Niemann-Pick disease (Imrie et al. 2015. PubMed ID: 26666848; http://www.hgmd.cf.ac.uk/). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Cataplexy;C0007758:Cerebellar ataxia;C0018681:Headache;C0264611:Speech apraxia;C0338656:Cognitive impairment;C1843921:Postural instability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 07, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.90
MVP		0.94
MPC		0.90
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.91

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: rs80358257; hg19: chr18-21118528;