dbSNP rs759075595: NPC1:p.Gln119ValfsTer8 (chr18-23568932-ACT-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000271.5(NPC1):c.352_353delAG(p.Gln119ValfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NPC1
NM_000271.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.29

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-23568932-ACT-A is Pathogenic according to our data. Variant chr18-23568932-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 370143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23568932-ACT-A is described in Lovd as [Pathogenic]. Variant chr18-23568932-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.352_353delAG	p.Gln119ValfsTer8	frameshift_variant	Exon 4 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 link	c.352_353delAG	p.Gln119ValfsTer8	frameshift_variant	Exon 4 of 25	1	NM_000271.5	ENSP00000269228.4		O15118-1
NPC1	ENST00000540608.5 link	n.266_267delAG		non_coding_transcript_exon_variant	Exon 2 of 16	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251408

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461704

Hom.:

AF XY:

0.00000550

AC XY:

AN XY:

727172

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:5

Dec 06, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000370143 / PMID: 10480349). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 09, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 10480349). This variant is present in population databases (rs759075595, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Gln119Valfs*8) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). ClinVar contains an entry for this variant (Variation ID: 370143). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type C

Pathogenic:1

Dec 04, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NPC1 c.352_353delAG (p.Gln119ValfsX8) variant results in a premature termination codon, predicted to cause a truncated or absent NPC1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1819C>T, p.Arg607X; c.3742_3745delCTCA, p.Leu1248fsX3). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/246198 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant has been reported in affected individuals in the literature, and one functional study showed the variant results in reduced mRNA due to non-sense mediated decay (Marcias-Vidal_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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