18-23552736-C-T

Variant names:

• chr18-23552736-C-T
• rs1055204017
• NM_000271.5:c.1554-1009G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000271.5(NPC1):​c.1554-1009G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.123
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-23552736-C-T is Pathogenic according to our data. Variant chr18-23552736-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 553804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1554-1009G>A		intron_variant	Intron 9 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1554-1009G>A		intron_variant	Intron 9 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.833+2022G>A		intron_variant	Intron 4 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1468-1009G>A		intron_variant	Intron 7 of 15	2
NPC1	ENST00000590301.1	n.229-1009G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:4

Apr 26, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 13, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Feb 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with biochemical and clinical features of Niemann-Pick type C disease (PMID: 20718790, 23593294, 25425405, 28480683, 29453517). This variant is also known as IVS9–1009G>A. ClinVar contains an entry for this variant (Variation ID: 553804). Studies have shown that this variant results in inclusion of a pseudoexon and introduces a premature termination codon (PMID: 19718781, 28167839). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC1-related disorder Pathogenic:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPC1 c.1554-1009G>A variant is predicted to interfere with splicing. This variant occurs within a deep intronic region and has been reported in the compound heterozygous state in patients with Niemann-Pick disease type C1 (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781; Patients SEQ1 and 2 in Hastings et al. 2019. PubMed ID: 31639011; Zeiger et al. 2018. PubMed ID: 29453517). A functional study has shown that the c.1554-1009G>A variant promotes a pseudoexon insertion and interferes with normal splicing (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic or likely pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/553804/). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	17
DANN	Benign	0.59
PhyloP100		0.12
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -1

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

Other links and lift over

dbSNP: rs1055204017; hg19: chr18-21132700;