rs28942108

Positions:

• chr18-23538651-G-A
• chr18-23538651-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000269228.10(NPC1):​c.2932C>T​(p.Arg978Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,700 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R978H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NPC1 ENST00000269228.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.52

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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000269228.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-23538651-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1519538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 18-23538651-G-A is Pathogenic according to our data. Variant chr18-23538651-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23538651-G-A is described in Lovd as [Pathogenic]. Variant chr18-23538651-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2932C>T	p.Arg978Cys	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.2932C>T	p.Arg978Cys	missense_variant	20/25	1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.2011C>T	p.Arg671Cys	missense_variant	13/18	2		ENSP00000467636
NPC1	ENST00000591075.1	n.565C>T		non_coding_transcript_exon_variant	2/3	4
NPC1	ENST00000591955.1	n.275C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251346 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000828 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 21, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 2976). This missense change has been observed in individual(s) with Niemann-Pick disease type C (NPC) (PMID: 11349231, 11479732, 15459971, 20718790, 22750297, 23427322, 23433426, 23774949, 26984608; Invitae). 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. This variant is present in population databases (rs28942108, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 978 of the NPC1 protein (p.Arg978Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant in a 15-year-old female with Niemann-Pick Type C -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals heterozygous for R978C and another pathogenic variant in NPC1 in association with variant Niemann-Pick disease type C biochemical phenotype and highly variable symptoms and age of onset, ranging from neonatal liver disease to gait ataxia and dysarthria at the age of 20 (Sun et al., 2001; Macias-Vidal et al., 2011; Di Leo et al., 2004; Abela et al., 2014; Perez-Poyato et al., 2012); This variant is associated with the following publications: (PMID: 22750297, 11349231, 15459971, 11479732, 26984608, 24035292, 20718790, 23433426, 28332184, 25425405, 31639011, 32138288, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2017	- -

Niemann-Pick disease, type C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2017

The p.Arg978Cys variant in NPC1 has been reported in 1 heterozygous individual with Parkinson disease and 9 individuals with the variant form and/or juvenile/adult onset of Niemann-Pick disease type C (Di Leo 2004, Kluenemann 2013, Macia-Vidal 2011, Perez-Poyato 2012, Riberio 2001, Schicks 2013, Sedel 2016, Stampfer 2013, Sun 2001). All of the 9 individuals also carried another variant in NPC1 in trans, with at least 2 being known disease-causing variants. It also segregated along with another variant in NPC1 in trans in 4 affected relatives from 3 families (Di Leo 2004, Kluenemann 2013). This variant has also been reported in ClinVar (Variation ID 2976). p.Arg978Cys variant has been identified in 1/9848 of Ashkenazi Jewish and 2/111684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs28942108). Although this variant has been seen in the general population, its frequency is low enough to be consistent with carrier frequency for Niemann-Pick disease type C. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for the variant form of Niemann-Pick disease type C in an autosomal recessive manner. ACMG/AMP Criteria applied: PM2; PM3_VeryStrong; PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.81
Sift	Benign	0.050	D
Sift4G	Uncertain	0.052	T
Polyphen		0.95	P
Vest4		0.68
MutPred		0.85		Loss of loop (P = 0.0374);
MVP		0.98
MPC		0.63
ClinPred		0.83	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28942108; hg19: chr18-21118615;