rs150334966

Variant names:

• chr18-23538572-G-A
• rs150334966
• NM_000271.5:c.3011C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1 PP2 PP5 BP4 BS1_Supporting BS2

The NM_000271.5(NPC1):​c.3011C>T​(p.Ser1004Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1004S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:6
• Conservation: PhyloP100: 8.06

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000271.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 171 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 1.0917 (below the threshold of 3.09). Trascript score misZ: 1.706 (below the threshold of 3.09). GenCC associations: The gene is linked to Niemann-Pick disease, type C1, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset.
• PP5: Variant 18-23538572-G-A is Pathogenic according to our data. Variant chr18-23538572-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326253.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=6}. Variant chr18-23538572-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3705725). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000736 (1076/1461878) while in subpopulation EAS AF = 0.00448 (178/39698). AF 95% confidence interval is 0.00395. There are 2 homozygotes in GnomAdExome4. There are 532 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.3011C>T	p.Ser1004Leu	missense_variant	Exon 20 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.3011C>T	p.Ser1004Leu	missense_variant	Exon 20 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.2087C>T	p.Ser696Leu	missense_variant	Exon 13 of 18	2		ENSP00000467636.1
NPC1	ENST00000591075.1	n.644C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4
NPC1	ENST00000591955.1	n.354C>T		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000684 AC: 172 AN: 251486 AF XY: 0.000728

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000736 AC: 1076 AN: 1461878 Hom.: 2 Cov.: 31 AF XY: 0.000732 AC XY: 532 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209 AC: 7 AN: 33480

Gnomad4 AMR exome AF: 0.000134 AC: 6 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00448 AC: 178 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00157 AC: 84 AN: 53418

Gnomad4 NFE exome AF: 0.000688 AC: 765 AN: 1112002

Gnomad4 Remaining exome AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74456

Gnomad4 AFR AF: 0.000313 AC: 0.000312831 AN: 0.000312831

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000578 AC: 0.000578481 AN: 0.000578481

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000848 AC: 0.000847777 AN: 0.000847777

Gnomad4 NFE AF: 0.00107 AC: 0.00107328 AN: 0.00107328

Gnomad4 OTH AF: 0.000474 AC: 0.000473934 AN: 0.000473934

Alfa AF: 0.000780 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:4 Uncertain:3

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1004 of the NPC1 protein (p.Ser1004Leu). This variant is present in population databases (rs150334966, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 11349231, 30119649; internal data). 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: 326253). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1004 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 32222928), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NPC1 gene c.3011C>T (p.Ser1004Leu) variant is a missense variant that is reported in two studies and found in a total of three individuals, including a sibling pair, with Niemann-Pick disease (NPC), all in a compound heterozygous state (Sun et al. 2001; Kawazoe et al. 2018). In the sibling pair, the p.Ser1004Leu variant was inherited from an unaffected father and was in trans with a frameshift variant inherited from the mother (Kawazoe et al. 2018). Control data are not available but the variant is reported at a frequency of 0.002268 in the European (Finnish) population of the Exome Aggregation Consortium. The Ser 1004 residue is located within the cysteine-rich region of the protein. Filipin staining of skin fibroblasts from one of the patients showed a staining pattern associated with NPC (Kawazoe et al. 2018). The evidence for this variant is limited. The p.Ser1004Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease. -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type C1 Niemann-Pick disease (MIM#257220) and type D Niemann-Pick disease (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been observed amongst individuals carrying the same pathogenic variant (PMID: 32138288). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (200 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ser1004Pro) has been observed in two individuals from one family with Niemann-Pick disease type C1 who also have p.(Ala927Val) (PMID: 32222928). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS and as likely pathogenic by clinical laboratories in ClinVar. It has also been observed in three individuals from two families with 'variant' or atypical Niemann-Pick disease type C1, one family was confirmed to be compound heterozygous, the other had a second variant but the phasing was not confirmed (PMIDs: 11349231, 30119649). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 11, 2017

Counsyl

Significance: Uncertain significance

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 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:2

Apr 29, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 11349231, 24386122, 30119649, 34426522, 35207755, 34830064, 33990640, 29867446, 32371106, 30503768, 12955717, 25764212, 39507854, 32138288, 32222928, 37032242) -

Aug 11, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC1: PM2, PM3, PM5, PP3, PS4:Supporting -

Niemann-Pick disease, type C Pathogenic:1

May 12, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NPC1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00068 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.00068 vs 0.0027), allowing no conclusion about variant significance. c.3011C>T has been observed in individual(s) affected with Niemann-Pick Disease Type C (Kawazoe_2018, Sun_2001, Internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30119649, 11349231, Internal data). ClinVar contains an entry for this variant (Variation ID: 326253). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

NPC1-related disorder Uncertain:1

Feb 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPC1 c.3011C>T variant is predicted to result in the amino acid substitution p.Ser1004Leu. This variant has been reported in patients with Niemann-Pick disease, however, its pathogenicity was not completely elucidated (Sun et al. 2001. PubMed ID: 11349231; Kawazoe et al. 2018. PubMed ID: 30119649). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretation in ClinVar ranging from uncertain to likely pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/326253/). Of note, a different variant impacting the same amino acid (p.Ser1004Pro) has been documented in patients with NPC1-related disorder (Supplemental Table 1 in Reunert. 2016. PubMed ID: 26981555). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.76
Sift	Benign	0.062	T
Sift4G	Benign	0.16	T
Polyphen		0.84	P
Vest4		0.93
MVP		0.95
MPC		0.29
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.49
gMVP		0.81
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150334966; hg19: chr18-21118536; COSMIC: COSV52578837; COSMIC: COSV52578837;