rs483352886

Positions:

• chr18-23554758-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000271.5(NPC1):​c.1553G>A​(p.Arg518Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,457,914 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to 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. R518W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense, splice_region
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.79

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain 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 chr18-23554759-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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 18-23554758-C-T is Pathogenic according to our data. Variant chr18-23554758-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23554758-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.1553G>A	p.Arg518Gln	missense_variant, splice_region_variant	9/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1553G>A	p.Arg518Gln	missense_variant, splice_region_variant	9/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.836G>A	p.Arg279Gln	missense_variant, splice_region_variant	4/18	2
NPC1	ENST00000540608.5	n.1467G>A		splice_region_variant, non_coding_transcript_exon_variant	7/16	2
NPC1	ENST00000590301.1	n.228G>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457914 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725540

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000458 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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:5

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.1553G>A (p.Arg518Gln) variant in NPC1 gene has been reported in multiple individuals affected with Niemann-Pick Disease Type C (Dardis et al., 2020; Mahmoud et al., 2019). Experimental studies have shown the variant to result in aberrant splicing resulting in a premature termination (Yamamoto et al.,1999). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic. The amino acid Arg at position 518 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg518Gln in NPC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	Shanghain Institute for Pediatric Research	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 22, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in exon 9 and introduces a premature termination codon (PMID: 10480349). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 132890). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 10480349, 24001525). This variant is present in population databases (rs483352886, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the NPC1 protein (p.Arg518Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2021	Observed with a second NPC1 variant in unrelated patients with Niemann-Pick disease type C in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some of these cases (Imrie et al., 2015; Costanza et al., 2020); Published functional studies suggest R518Q leads to incomplete alternative splicing resulting in loss of function transcript (Yamamoto et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26666848, 10480349, 24001525, 32138288, 32482919) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -

Niemann-Pick disease, type C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 30, 2021

Variant summary: NPC1 c.1553G>A (p.Arg518Gln) 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. Experimental studies have shown the variant to result in abberant splicing resulting in a premature termination (Yamamoto_1999). The variant allele was found at a frequency of 4e-06 in 250980 control chromosomes. c.1553G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (Yamamoto_1999, Dardis_2020, Mahmoud_2019, etc). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. 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	0.087
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.054
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.78	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.24
Sift	Benign	0.64	T
Sift4G	Benign	0.61	T
Polyphen		0.020	B
Vest4		0.71
MutPred		0.51		Loss of solvent accessibility (P = 0.0769);
MVP		0.86
MPC		0.32
ClinPred		0.36	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.070		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: rs483352886; hg19: chr18-21134722;